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ANTINEOPLASTICANTINEOPLASTIC
AGENTSAGENTS
Dr. Ravisankar
M.
Pharm., PhD.
Vignan pharmacy college ,
Vadlamudi-522 213, A.P., India.
Introduction and HistoryIntroduction and History
 The medical term for tumor (or) cancer isThe medical term for tumor (or) cancer is
NeoplasmNeoplasm, Which means a relatively autonomous growth, Which means a relatively autonomous growth
(or) uncorodinated cell proliferation of body tissue.(or) uncorodinated cell proliferation of body tissue.
 The term Neoplasm meansThe term Neoplasm means New growthNew growth and theand the
process of cell proliferation is calledprocess of cell proliferation is called NeoplasiaNeoplasia..
 The branch of medicine which deals with theThe branch of medicine which deals with the
excessive study of neoplasm (tumor) and itsexcessive study of neoplasm (tumor) and its
development diagnosis and treatment is calleddevelopment diagnosis and treatment is called
““Oncology.Oncology.””
 The term cancer was translated from aThe term cancer was translated from a Latin wordLatin word
carcino i.e. Crabcarcino i.e. Crab by celsus.by celsus.
 For the first time Hippocrates coined the Greek wordFor the first time Hippocrates coined the Greek word
Karkinos i.e. (crab/cray fish)Karkinos i.e. (crab/cray fish) for malignant breast cancer.for malignant breast cancer.
Classification of tumorsClassification of tumors
 Tumor is general term for any abnormal mass orTumor is general term for any abnormal mass or
growth of tissue which is not necessarily lifegrowth of tissue which is not necessarily life
threatening, where as cancerous tumor is athreatening, where as cancerous tumor is a
malignant neoplasm, which is highly dangerous.malignant neoplasm, which is highly dangerous.
 Tumor is classified in toTumor is classified in to twotwo categories.categories.
a.a. Malignant tumorMalignant tumor. (. (a disease or a growth that is likely to geta disease or a growth that is likely to get
uncontrollably worse and lead to death)uncontrollably worse and lead to death)
b.b. Non-Malignant tumorNon-Malignant tumor oror benignbenign tumor(tumor(a growtha growth
that is not likely to cause death)that is not likely to cause death) or also known as non-or also known as non-
cancerous tumor which does notcancerous tumor which does not metasmetastatasizesize..
 MetasMetastata(i)(i)
sis is secondary tumor or growthsis is secondary tumor or growth
originating from the primary tumor and may groworiginating from the primary tumor and may grow
elsewhere in the body.(elsewhere in the body.(If cancer cells metastasize, theyIf cancer cells metastasize, they
spread to other parts of the body and cause tumours (= a mass of cells)spread to other parts of the body and cause tumours (= a mass of cells)
to grow there.to grow there.
Largest tumor ever removedLargest tumor ever removed According to Guinness WorldAccording to Guinness World
Records, the biggest tumorRecords, the biggest tumor
ever removed intact from theever removed intact from the
human bodyhuman body weighed in atweighed in at
303 pounds303 pounds (137.6 kg)(137.6 kg) andand
measuredmeasured 3 feet (1 m)3 feet (1 m) inin
diameter.diameter.
 The tumor, located on theThe tumor, located on the
right ovaryright ovary, was removed in, was removed in
19911991 during an operationduring an operation
performed by Professorperformed by Professor
Katherine O’Hanlan atKatherine O’Hanlan at
Stanford University MedicalStanford University Medical
Center in CaliforniaCenter in California ..
 The operation to remove theThe operation to remove the
tumor from the abdomen oftumor from the abdomen of
an unnamedan unnamed 34-year-old34-year-old
womanwoman took overtook over six hourssix hours
to complete.to complete.
 TheThe pathologypathology reportreport
concluded that the tumorconcluded that the tumor
waswas benignbenign. The patient. The patient
made a full recovery, andmade a full recovery, and
reportedly did not seekreportedly did not seek
treatment sooner due totreatment sooner due to
being bed-ridden andbeing bed-ridden and
suffering fromsuffering from agoraagoraphobiaphobia
China’s elephant man grows world’s
Largest tumor on face.(33 pounds)
The man-with-no-face.
Tumor growth and kineticsTumor growth and kinetics
 The principle difference between mature of normal tissueThe principle difference between mature of normal tissue
and tumors is …and tumors is …
 The rate of cell replication i.e. proliferation for mostThe rate of cell replication i.e. proliferation for most
normal tissues equals the rate of cell death (normal tissues equals the rate of cell death (a balance isa balance is
maintained between cell renewal and cell apoptosismaintained between cell renewal and cell apoptosis
(programmed cell death),(programmed cell death), where as in neoplasmwhere as in neoplasm
proliferation exceeds the cell death.proliferation exceeds the cell death.
 Proliferation in normal tissueProliferation in normal tissue responds to subtle signalsresponds to subtle signals
that indicate when proliferation is needed repair,that indicate when proliferation is needed repair,
regeneration or growth and developmentregeneration or growth and development. But .... But ...
 Neoplasm seem toNeoplasm seem to lack such an auto regulationlack such an auto regulation ofof
proliferation and the cell replication rate i.e. new cellsproliferation and the cell replication rate i.e. new cells
replace the old cells by differentiation mechanism.replace the old cells by differentiation mechanism.
Occasionally due to carcinogens
(cancer causing agents) one of the
Cell get mutated and does not
respond to normal growth control
mechanisms.
This mutated cell undergoes further
mutations and transforms i.e.
to Converts in to tumor cell which
starts proliferating vigorously.
This in turn results in a mass of
abnormal cells (tissues) called tumour
or neoplasm.
SIGNALS LEADING TO APOPTOSISSIGNALS LEADING TO APOPTOSIS
cells no longer
listen to the signals
(In case of cancer
cells)
ANGIOGENISISANGIOGENISIS
•Angiogenesis is the process by which tumours growth of new blood vessels to provide the nutrients
required for continued growth.
•As tumour grows, its cancerous cells Require a steady supply of amino acids, nucleic acid bases,
carbohydrates, oxygen, And growth factors, if they are to continue multiplying. This means that
the tumour has to have a good blood supply.
• As a tumour grows in size, however, its cells become increasingly far away from the blood supply and
become starved of these resources. This is particularly true for the cells in the centre of the tumour.
•In order to counter This, tumour cells release growth factors such as vascular endothelial growth
factor (VEGF) and fibroblast growth factor (FGF-2) which interact with receptors on the
Endothelial cells of nearby blood vessels and stimulate these cells to divide, leading to the branching and
extension of existing capillaries – a process known as angiogenesis.
•Agents which inhibit angiogenisis( angiostatin and thrombospondin) are useful in anticancer therapy to
inhibit growth and to enhance the effectiveness of other drugs.
(If the cancer cells invade other parts
Of body and set up secondary tumours
—
A process known as metastasis
Newly developing
Endothelial cells release protein
release
grwth factors
As
grows
Genarally in all the organs and tissues of
human beings a balance is maintained b/n
cell renewal and cell apoptosis(programmed
cell death).
New cells replace the old cells by proliferation
and differentiation mechanisms.
Occasionally, due to carcinogens
(cancer causing agents) one of the cells
get mutated and does't respond to
normal growth control mechanisms.
This mutated cell undergoes further
mutations and transforms in to tumour
cell which starts poliferating vigorously.
subsequently a mass of abnormal cells
(tissues) called neoplasm or tumour.
(vascular endothelial growth factor)
one of the
cell get
mutated
and FGF-2
Doubling timeDoubling time The doubling time is theThe doubling time is the mean (“average”) interval betweenmean (“average”) interval between
successive mitoses.successive mitoses.
 It is a characteristic of the particular type of tumor cell. DoublingIt is a characteristic of the particular type of tumor cell. Doubling
time varies markedly among various kinds of tumors.time varies markedly among various kinds of tumors.
 Burkitt’s tumor = it is approximately 24hours.Burkitt’s tumor = it is approximately 24hours.
 In acute leukemia = 2 weeks.In acute leukemia = 2 weeks.
 In breast cancer = 3 months.In breast cancer = 3 months.
 In multiple myeloma = 6 to 12 months.In multiple myeloma = 6 to 12 months.
 Mucosal cells of the rectum every 24 hours.Mucosal cells of the rectum every 24 hours.
 A tumor cell becomes detectable when the number of cells reachesA tumor cell becomes detectable when the number of cells reaches
about 10about 1099
to 10to 101010
cells. This requirescells. This requires 30 to 3330 to 33 doubling times.doubling times.
 The neoplasm becomes lethal when the population reaches aboutThe neoplasm becomes lethal when the population reaches about
5x105x101111
to 5x10to 5x101212
cells, aftercells, after 3939 toto 4242 doubling times.doubling times.
Death mainly arises, due to the competition between normal and cancer cells
for nutrition, blood supply etc as the cancer cells are rapidly dividing their
number exceeds the normal cells and take away all the nutrients and make the
normal cells to starve. As a result the normal cell functions are hindered and
ultimately the organ becomes functionless, simply the cancer cells are
parasites on normal cells. Moreover the cancer cells secrete no or more
hormones that alters the homeostasis of the body.
 CANCER STATISTICS.CANCER STATISTICS.
According toAccording to World Cancer ReportWorld Cancer Report from the International Agency for Research onfrom the International Agency for Research on
Cancer, cancer is projected to the leading cause of death in 2010. There were anCancer, cancer is projected to the leading cause of death in 2010. There were an
estimated 12 million new cancer diagnoses and more than 7 million deaths worldwideestimated 12 million new cancer diagnoses and more than 7 million deaths worldwide
this year. according to WHO “Cancer is a leading cause of death worldwide: itthis year. according to WHO “Cancer is a leading cause of death worldwide: it
accounted for 7.4 million deaths (around 13% of all deaths) in 2004.”accounted for 7.4 million deaths (around 13% of all deaths) in 2004.”
 lung (1.3 million deaths/year)lung (1.3 million deaths/year)
 stomach (803 000 deaths)stomach (803 000 deaths)
 colorectal (639 000 deaths)colorectal (639 000 deaths)
 liver (610 000 deaths)liver (610 000 deaths)
 breast (519 000 deaths).breast (519 000 deaths).
 Among men - lung, stomach, liver, colorectal, oesophagus and prostateAmong men - lung, stomach, liver, colorectal, oesophagus and prostate
 Among women - breast, lung, stomach, colorectal and cervicalAmong women - breast, lung, stomach, colorectal and cervical
 IN INDIA 1 OUT OF 2 MENIN INDIA 1 OUT OF 2 MEN
 1 OUT OF 3 WOMEN1 OUT OF 3 WOMEN
 1 OUT OF 4 DEATHS IN THIS COUNTRY1 OUT OF 4 DEATHS IN THIS COUNTRY
 is currently from cancer.is currently from cancer.
CAUSES OF CANCERCAUSES OF CANCER
 There are several agents responsible for cancer.There are several agents responsible for cancer.
The agents (The agents (physical, chemical and biological)physical, chemical and biological) which causes cancer are calledwhich causes cancer are called
carcinogenscarcinogens..
1.1. Physical agentsPhysical agents: UV and ionizing radiations (x-ray, gamma and alpha and beta: UV and ionizing radiations (x-ray, gamma and alpha and beta
rays cause cancer, uv rays of sunlight, nuclear fission. These radiations haverays cause cancer, uv rays of sunlight, nuclear fission. These radiations have
mutagenic effect.mutagenic effect.
Ex: Leukaemias, skin, lung, breast, osteosarcoma, thyroid cancer.Ex: Leukaemias, skin, lung, breast, osteosarcoma, thyroid cancer.
2.2. Biological agentsBiological agents::
a.a. Bacterial agentsBacterial agents: peptic ulcers and chronic gastritis and if these are left untreated: peptic ulcers and chronic gastritis and if these are left untreated
for a long time leads to gastric cancer.for a long time leads to gastric cancer.
b.b. Fungal agentsFungal agents: The fungus: The fungus Aspergillus flavusAspergillus flavus releasesreleases aflaaflatoxins in stored foodtoxins in stored food
and grains. If this contaminated food is consumed (espicially by Hepatitis B virusand grains. If this contaminated food is consumed (espicially by Hepatitis B virus
infected patients) it leads to hepatocellular carcinoma.infected patients) it leads to hepatocellular carcinoma.
c.c. Viral agents:Viral agents: Cervical cancer, Burkitt’s lymphoma, hairy cell lukaemia, HaepaticCervical cancer, Burkitt’s lymphoma, hairy cell lukaemia, Haepatic
carcinoma.carcinoma.
3.3. Chemical agentsChemical agents:: Alkylating agents, The acylating agents, PolyaromaticAlkylating agents, The acylating agents, Polyaromatic
hydrocarbons, Aniline,hydrocarbons, Aniline,
arsenic,anthracenes,dimethylsulphate,diepoxybutane,acetyl imidazole, dimethylarsenic,anthracenes,dimethylsulphate,diepoxybutane,acetyl imidazole, dimethyl
carbamyl chloride.carbamyl chloride.
4.4. Genetic factorsGenetic factors:: Genetic inheritance plays a key role in causing some of theGenetic inheritance plays a key role in causing some of the
cancers (breast carcinoma,retino blastinoma.cancers (breast carcinoma,retino blastinoma.
5.5. Diet and habitsDiet and habits: People taking rich in fats, low fibre content, stored grains.: People taking rich in fats, low fibre content, stored grains.
Alcoholism, smoking, chewing tobacco and betel nut .Alcoholism, smoking, chewing tobacco and betel nut .
6.6. Hormones and DrugsHormones and Drugs: Taking excessive oestrogens during the times of: Taking excessive oestrogens during the times of
pregancy(Vaginal endometrial cancer is prevalent in the girls born to the mothers)pregancy(Vaginal endometrial cancer is prevalent in the girls born to the mothers)
 7.Epidemio7.Epidemiological factorslogical factors::
a.a. Geographical and Racial factorsGeographical and Racial factors::
Climate, soil, diet habit and customs etc. Genetic composition alsoClimate, soil, diet habit and customs etc. Genetic composition also
influence the variations in cancer.influence the variations in cancer.
Ex: Breast cancer in prevalent in American women.Ex: Breast cancer in prevalent in American women.
Gastric carcinoma is in Japanese.Gastric carcinoma is in Japanese.
b.b. Environmental and cultural factorsEnvironmental and cultural factors: Exposure to industrial: Exposure to industrial
contaminants, smoke and radioactive metals.contaminants, smoke and radioactive metals.
Cancer ofCancer of pepenisnis is very rare in Muslims and jews due to theis very rare in Muslims and jews due to the
custom ofcustom of circumcircumcisioncision and their female partners are less likely toand their female partners are less likely to
suffer(prone) to cancer of cervix.suffer(prone) to cancer of cervix.
c.c. Age and sexAge and sex:: High risk of cancer is incident at an older age due toHigh risk of cancer is incident at an older age due to
reduction in immunity. It is usually seen in 5reduction in immunity. It is usually seen in 5thth
decade of life.decade of life.
Men are more prone toMen are more prone to lung cancerlung cancer while women are susceptiblewhile women are susceptible
toto breast cancerbreast cancer..
ANTINEOPLASTIC AGENTSANTINEOPLASTIC AGENTS
 Antineoplastic agents are the drugs which are used in toAntineoplastic agents are the drugs which are used in to
management of malignant disease (i.e. cancer)management of malignant disease (i.e. cancer)
 Antineoplastic agents are also known asAntineoplastic agents are also known as Cytotoxic agents.Cytotoxic agents.
cancer is a very difficult disease to treat. This has been becausecancer is a very difficult disease to treat. This has been because
ofof lack of reliable diagnostic tests for the early detectionlack of reliable diagnostic tests for the early detection andand notnot
having the compounds which will cure any form of cancerhaving the compounds which will cure any form of cancer..
Anticancer drugs used in the treatment of malignant diseaseAnticancer drugs used in the treatment of malignant disease
when surgery or radiotherapy is not possible or has provedwhen surgery or radiotherapy is not possible or has proved
ineffective. They are also employed asineffective. They are also employed as
adjunct to surgery or Radiotherapy. They are used asadjunct to surgery or Radiotherapy. They are used as
the initial treatment as in laeukaemia.the initial treatment as in laeukaemia.
Chemotherapy usually involves combinations of drugs havingChemotherapy usually involves combinations of drugs having
different targets or mechanisms of action.Traditional anticancerdifferent targets or mechanisms of action.Traditional anticancer
drugs are generally cytotoxic more modern drugs aredrugs are generally cytotoxic more modern drugs are
selective in their action.selective in their action.
TREATMENT OF CANCERTREATMENT OF CANCER
 Cancer can be treated by the following means:Cancer can be treated by the following means:
 1. Surgery1. Surgery
 2. Radiation therapy2. Radiation therapy
 3.Immunotherapy3.Immunotherapy
 4.Hormonal therapy4.Hormonal therapy
 5.Antibiotics5.Antibiotics
 6.Chemotherapy6.Chemotherapy
Chemotherapy is the term applied for a wide range of chemicalChemotherapy is the term applied for a wide range of chemical
substances i.e. drugs that are employed in the treating the cancer.substances i.e. drugs that are employed in the treating the cancer.
These drugs may act by various mechanisms likeThese drugs may act by various mechanisms like
 Interfering with the replication of DNA.Interfering with the replication of DNA.
 Inhibiting the formation of important molecules which areInhibiting the formation of important molecules which are
needed for DNA formation.needed for DNA formation.
 Inhibiting the mytotic spindle.Inhibiting the mytotic spindle.
Infact, most of traditional Anticancer agentsInfact, most of traditional Anticancer agents
now-a- days available which….now-a- days available which….
 Increase survival time.Increase survival time.
 Supress the growth of developing neoplasmSupress the growth of developing neoplasm
 Sprerading of the disease from one place toSprerading of the disease from one place to
another place.another place.
 Relief of pain upto some extent.Relief of pain upto some extent.
 Immunosuppressive agents are also used toImmunosuppressive agents are also used to
prolong the life of organs and tissueprolong the life of organs and tissue
transplants during surgical procedural methodstransplants during surgical procedural methods
in cancer.in cancer.
Classification of Antineoplastic drugsClassification of Antineoplastic drugs
 Cytotoxic drugs:Cytotoxic drugs:
 A.A. Alkylating agentsAlkylating agents ::
1.Mustard drugs:1.Mustard drugs: Mechlorethamine,Mechlorethamine, Chlorambucil,Chlorambucil, Cyclophosphomide, MelphalanCyclophosphomide, Melphalan ..
2.2. AziridinesAziridines :: Thiotepa.Thiotepa.
3.3. Alkyl sulphones:Alkyl sulphones: Busulphan.Busulphan.
4. Nitrosoureas :4. Nitrosoureas : Lomustine,(CeeNU)Lomustine,(CeeNU)
CarmustineCarmustine.(BiCNU).(BiCNU)
Procarbazine.Procarbazine.
B.B. AntimetabolitesAntimetabolites ::
Purie antagonists:Purie antagonists: 6-Mercaptopurine.6-Mercaptopurine.
Folic acid antagonist:Folic acid antagonist: Methotrexate.Methotrexate.
Pyrimidine antagonist:Pyrimidine antagonist: 5-Fluorouracil.5-Fluorouracil.
C.C. Plant productsPlant products : 1. Vinka alkaloids.: 1. Vinka alkaloids.
a.a. Vincristine b. VinblastineVincristine b. Vinblastine..
2.Taxanes: Paclitaxel,2.Taxanes: Paclitaxel, DoceDocetaxel.taxel.
D.D. AntibioticsAntibiotics: Dactinomycin, Daunorubicin, Doxorubicin, Mitomycin.: Dactinomycin, Daunorubicin, Doxorubicin, Mitomycin.
E.E. RadioisotopesRadioisotopes: Radioiodine I: Radioiodine I131131
, Radiophosphorus P, Radiophosphorus P3232
..
Mechanism of actions of anticancer agentsMechanism of actions of anticancer agents
Alkylating agentsAlkylating agents ::
1.Mustard drugs1.Mustard drugs : Mechlorethamine,: Mechlorethamine, Chlorambucil,Chlorambucil, Cyclophosphomide, MelphalanCyclophosphomide, Melphalan
Nitrogen mustards get their name because they are related to the sulfur-containing
Mustard gases used during First world War. The nitrogen mustard compound
Chlormethine was the first alkylating agent to be used medicinally in 1942.
If second alkyl halide is reacts with
Water,but the crosslinking is major factor
Chlormethine (Mechlorehtamine) is highly reactive
To servive oral route and has to be
Administered I.V. The side reaction can
Be reduced by putting aromatic ring
On the N atom instead of methyl group.
The lone pair of nitrogen interacts with the pi system of the ring and
Less available to displace the cl ion. As a result aziridinium ion less
easily formed than only strong nucleophile guanine will react with it
The melphalan takes this advantage of this property.
cyclophosphomide
LauncherCH3
Missile
(odour resembling mustard,garlic plant hence the name given)
Mechlorethamine(mustine,Nitrogenmustard)Mechlorethamine(mustine,Nitrogenmustard)
 Metabolism:rapid hydrolysis by body fluids and demethylation in liverMetabolism:rapid hydrolysis by body fluids and demethylation in liver
 active metabolite(s)yes; ethylenimonium derivative.active metabolite(s)yes; ethylenimonium derivative.
MECHANISM OF ACTION:
Mechlorethamine, a bifunctional alkylating agent, interferes with DNA
replication and RNA transcription as the result of formation of unstable
carbonium ions which form interstrand cross-links with DNA, likely binding at
the N7
position of guanine. Mechlorethamine has weak immunosuppressive
properties. Mechlorethamine is cell cycle phase-nonspecific; however, its
effect is most pronounced in the S phase, and cell proliferation is arrested in
the G2 phase.
Topical activity of mechlorethamine may also involve immune mechanisms.
Alkylating agents Contains ractive alkyl
Groups. These compounds Produce highly
reactive Carbonium ion intermeadiates
Which form covalent bonds
By alkylation with nucleophilic
Groups react with the 7th
Position of guanine in
each of The double starnds of DNACausing
croslinking/mispairing.
This interferes in the separation
of strands and prevents mitosis or arrest cell
replication.
Alkylating agents (DNA cross linging agents)Alkylating agents (DNA cross linging agents)
Mechanism of actionMechanism of action
Alkylation is defined as replacement of hydrogen on an atom by an alkyl group.
nu - H + alkyl-Y ---------- alkyl – nu + H+
+ Y -
7 7
DNA cross-linking agents such
as nitrogen mustards are highly
electrophillic (δ+
) structures.
When encountered the
nucleophillic groups on various
DNA bases(N7
of the guanine)
readily attack the electrophilic
drug, resulting in irreversible
alkylation or complexation of the
DNA base.
 Mechanism of ActionMechanism of Action
 Alkylating agents work by three different mechanisms: 1)Alkylating agents work by three different mechanisms: 1)
attachment of alkyl groups to DNA bases, resulting in theattachment of alkyl groups to DNA bases, resulting in the
DNA being fragmented by repair enzymes in theirDNA being fragmented by repair enzymes in their
attempts to replace the alkylated bases, preventing DNAattempts to replace the alkylated bases, preventing DNA
synthesis and RNA transcription from the affected DNA,synthesis and RNA transcription from the affected DNA,
2) DNA damage via the formation of cross-links (bonds2) DNA damage via the formation of cross-links (bonds
between atoms in the DNA) which prevents DNA frombetween atoms in the DNA) which prevents DNA from
being separated for synthesis or transcription, andbeing separated for synthesis or transcription, and
 3) the induction of mispairing of the nucleotides leading3) the induction of mispairing of the nucleotides leading
to mutations.to mutations.
Alkylating agents are so named because of their ability to add alkyl groups to
many electronegative groups under conditions present in cells. They stop
tumor growth by cross-linking guanine bases in DNA double-helix strands -
directly attacking DNA. This makes the strands unable to uncoil and separate.
As this is necessary in DNA replication, the cells can no longer divide.
double stranded DNA has two strands
A phosphate-deoxyribose polymer composes the
backbone of the DNA
adjacent sugars are connected by phosphodiester bonds
nitrogenous bases are convalently bonded to the 1'
carbon of the deoxyribose
the two DNA strands are antiparallel
the two strands are held together by hydrogen bonds
between complementary bases
adenine hydrogen bonds (base pairs) to thymine
guanine hydrogen bonds to cytosine
Components of DNA:
Alkylation of DNA by the nitrogen mustard compound chlormethineAlkylation of DNA by the nitrogen mustard compound chlormethine
Alkylating agents
Contains reactive alkyl
Groups .These compounds
Produce highly reactive
Carbonium ion intermeadiates
Which form covalent bonds
By alkylation with nucleophilic
Groups react with the 7th
Position of guanine in each of
The double starnds of DNA
Causing cross
linking/mispairing.
This interferes in the separation
of strands and prevents
mitosis or arrest cell
replication
Undergoes neibhobouring group reactions to form
Stained 3 membered onium , ethylene imminium ion or
Aziridinium ions, which react with guanine groups on
DNA To produce cross-linking.
If second alkyl halide reacts with
Water Cross linking is the major factor
carbocations are
highly reactive
(The 2 chlorine atoms are dramatically decrease the basic strength of amino N through
strong electro -ve inductive effect.)
un-ionized amine forms aziridinium ion.
δ+
 Structure activity relation ship:Structure activity relation ship:
Cl-CH2-CH2-N-CH2-CH2-Cl
R
Bis-Beta haloalkylamine.
The R group can be either
alipatic or aromatic, is the main
determinant of chemical reactivity
oral bioavailability,and the nature
and extent of side effects.
Aliphatic nitorgen substituent(-CH3)
will push electrons to the amine through
sigma bonds. This electronic enrichment
enhances the Nucleophilic character of the
lone pair of electrons and increase the
speed at which the β-carbon of the mustared
will be attacked.
whether the tumor cell or a healthy cell ,
the aziridinium ion as soon it forms will react
with cell nucleophiles such as
electron rich NH,OH, SH groups.
The body water also can react with
aziridinium ion. So intra and inter molicular
reactions happens so rapidly almost no
chance of exists for tissue or cell specificity.
which means increased risk of serious side effects
and toxicity.
An aromatic N substituent
(Phenyl)group conjugated
with the mustard nitrogen
will stabilize the lone
pair of electrons through
rosonance.
It slows the intramolecular
nucleophilic attack,aziridinium
ion formation and DNA alkylation
αβ α β
(aromatic mustards have less
side effects and oral administration)
Ex:melphalan,chlorambucil.
here attack of electrophilic beta corbon
is very slow because formation of
aziridinium ion also significantly
delayed. DNA alkylation is controlled
and the drug can be given orally.
Nitrogen mustards can decompose in
aqueous media through formation of
the inactive dehalogenated diol.
the oxygen of water can act as nucleophiles
to advance this degradative process.
so buffering solutions to a slightly acidic pH
helps to enhance stability in aqueous solution.
Some DNA alkylating agents such as nitrogen mustards and nitrosoureas are bifunctional
meaning that one molecule of the drug can bind two distinct DNA bases and DNA
cross-linking through two guanine N7
atoms results.
Nitrogen mustards are bis(β-haloalkyl) amines.
bis- means two; halo (short for halogen) here chlorine.
The 2 chlorine atoms decreases the basic strength of the amino N through a strong
inductive effect.
The unionized amine (two lone pair of electrons) that allows the formation of the highly
electrophilic aziridinium ion.
Mechanism of action:
The lone pair of electrons on the un-ionized amino group conducts an intramolecular
nucleophilic attack at the β-carbon of the mustard, displacing chloride ion and forms
highly reactive electrophilic aziridinium ion,a quaternary amine salt.
The stained cyclic structure are highly electrophilic because of the strong -ve inductive
effectve of the +ve charged N atom.
DNA nucleophile conducts an intermolicular nucleophilic attack which breaks the
aziridine ring and alkylates DNA.
Here guanine is the nucleic acid base involved in the alkylation reaction.
when aziridinium ring cleaves lone pair of electrons are regenerated on mustard nitrogen.
In the same way second arm of the mustard and second molecule of DNA.
Ultimately 2 molecules of DNA(guanine) will be cross-linked through the nitrogen
mustard. mustard's drug hold covalently that's why unable to replicate DNA eventually
cell death is invitable If this. is happening in a tumor cell, the therapeutic goal is
accomplished. If this is happening in the healthy cell patient may experience side effects.
ChlorambucilChlorambucil
Solid, white, odourless, Insoluble in water, freely soluble in alcohol,acetone,
Chloroform. M.P=64 to 66C.
Physico - chemical properties
Mechlorethamine is highly reactive and forms mono alkylation of DNA guanine units also possible. If second alkyl halide reacts
With water, but the cross linking is major factor by which these drugs inhibit replication and acts as anticancer agents.
This side reactions mentioned above can be reduced by lowering the reactivity of the alkylating agent by attaching
Electron- withdrawing groups to the nitrogen to increase selectivity against DNA over proteins.
Chlorambucil acts by cross linking of DNA which results in formation of altered proteins leading to decrease in cell division
That ultimately causes death of the cell.
Toxic effects: Anaemia,neutropenia,thrombocytopenia,nausia,vimiting,diarrhoea,appetite,sterility,confusion.
Hallucinations . Skin reactions like rashes ,skin blistering and hepatotoxicity can also occur.
 Mechanism of Action
 Chlorambucil is an aromatic nitrogen mustard derivative which acts as a bifunctional
alkylating agent.
 Alkylation takes place through the formation of a highly reactive ethylenimonium
radical. A probable mode of action involves cross-linkage of the ethylenimonium
derivative between 2 strands of helical DNA and subsequent interference with
replication
 Metabolism
 The metabolism of chlorambucil in man appears to be similar to that in laboratory
animals and involves S-oxidation of the butyric acid side chain. Bis-2-chlorethyl-2(4-
aminophenyl) acetic acid
 [ phenylacetic acid mustard ( PAAM ) ] is a major metabolite of chorambucil. In a
study of 12 patients

 administered chlorambucil 0.2mg/kg bodyweight orally, the mean dose adjusted-peak
plasma concentration of PAAM ( 306 + 73 ng/ml ) was reached within 1 – 3 hours.
The mean terminal elimination plasma half-life was 1.8 + 0.4 hours. The significant
contribution of PAAM to the alkylating activity of drug was evident as the mean area
under the plasma concentration time curve (AUC) of PAAM was approximately 1.33
times greater than the AUC of chlorambucil.
Phenyl acetic acid mustard (an active
chlorambucil metabolite)
 SAR of chlorambucil:SAR of chlorambucil:
This aromatic ring is able to stabilize the lone pair of
electrons on the mustard N through resonance with
conjugated phenyl ring, slowing the formation of reactive
aziridinium ion.
Because the lone pair of electrons of clorambucil and other
aromatic mustards is less reactive,there is a greater
opportunity for distribution to cancer cells and a decreased
incidence of severe side effects.
This group (bis-β haloalkyl amine) is bifunctional
(one molecule of the durg can bind tow distinct DNA
bases) are very important for chemical reactivity of the drug.
 LEUKERAN  Tablets
 Chlorambucil Tablets 2mg and 5mg .
Therapeutic Indications
LEUKERAN is indicated in the treatment of:-
• Hodgkin's disease
• certain forms of non-Hodgkin's lymphoma
• chronic lymphocytic leukaemia
• Waldenstrom's macroglobulinaemia
• Advanced ovarian adenocarcinoma
Leukeran has a significant therapeutic effect on a proportion of patients with breast
cancer.
Multiple myeloma,
Lymphosarcoma,Lymphocytic leukemia,
Overian adenocarcinoma, testicular cancer.
Busulphan(myleran)Busulphan(myleran)
Busulphan is a cytotoxic drug belonging to the group of alklating agent. It
Is chemically, busulfan is classified as an alkyl sulfonate.
Mechanism of action:
Busulphan is a bifunctional alkylating agent. In alkylation the sulphonate groups are good leaving
groups and play a similar role to the Chlorines in the nitrogen mustards. The mechanism
involves a direct SN2 Nucleophilic substitution of the sulfonate groups and does not involve
an Intermediate similar to the aziridinium ion, The N-7 position of guanine residues is the
most susceptible site for this reaction to form interstrand cross-linking. It Exerts its cytotoxic
action by reacting with guanosine at N-7 position thereby Interfering with the replication of
RNA as well.
sulSulfonate groups are good leaving groups.
Buslfan-mediated DNA alkylation:
7
7
 Busulphan:
 MECHANISM OF ACTION:
 Busulfan is a bifunctional alkylating agent. Following systemic absorption, carbonium
ions are rapidly formed, resulting in alkylation of DNA. This leads to breaks in the
DNA molecule as well as cross-linking of the twin strands, resulting in interference of
DNA replication and transcription of RNA. The antitumour activity of busulfan is cell
cycle phase-nonspecific.
 Metabolism: extensive hepatic metabolism, with CYP3A4 involvement; at
least 12 metabolites identified with unknown activity
 active metabolite(s) none known
 inactive metabolite(s) 25-35% as methanesulfonic acid

Synthesis ofSynthesis of bubusulphansulphan
Physico chemical properties:
Solid, white, odourless,veryslightly soluble in water,alcohol,ether, and freely soluble in
Acetone and chloroform. M.P =114 to 1180
c.
Toxic effects: Serious bone marrow hypoplasia and myelosuppression are possibe with this agent,recovery
from busulfan-induced panctopenia can take up to 2 years.
Nausea , headache,constipation,flushing fever,irregular heart beat,
Chest pain,blurred vision. Rashes ,iching,swelling and sterility can also occur.
Therapeutic uses:
1.It is used in the treatment of chronic granulocytic leukemia and may
increase the life expectancy of patients by about a year.
2. Chronic Myelogenous leukemia.
3. Disorders of bone marrow like severy thrombocytosis, myelofibrosis,
polycythemia vera.
Dose: orally 0.3mg/kg to a maximum of 4mg/kg daily. (or) by IV infusion.
CARMUSTINECARMUSTINE
Brand name (BiCNU):Brand name (BiCNU):
 BiCNU® (carmustine) is one of the nitrosoureas used in the treatment ofBiCNU® (carmustine) is one of the nitrosoureas used in the treatment of
certain neoplastic diseases.certain neoplastic diseases.
 It is 1,3-bis (2-chloroethyl)-1-nitrosourea.It is 1,3-bis (2-chloroethyl)-1-nitrosourea.
 It is lyophilized pale yellow flakes or congealed mass with a molecularIt is lyophilized pale yellow flakes or congealed mass with a molecular
weight of 214.06.weight of 214.06.
 It is highly soluble in alcohol and lipids, and poorly soluble in water.It is highly soluble in alcohol and lipids, and poorly soluble in water.
 BiCNU is administered by intravenous infusion after reconstitution asBiCNU is administered by intravenous infusion after reconstitution as
recommended.recommended.
1,3-bis (2-chloroethyl)-1-nitrosourea.1,3-bis (2-chloroethyl)-1-nitrosourea. ( BiCNU)Iupac name:
1 32
Nitrasoureas:Nitrasoureas:
CarmustineCarmustine
Carmustine and lomustine are examples ofCarmustine and lomustine are examples of
chloroethylnitrasoureaschloroethylnitrasoureas
Which are lipid soluble and can cross the blood-Which are lipid soluble and can cross the blood-
brain barrier. As a result they have beenbrain barrier. As a result they have been
used in the treatment of brain tumours andused in the treatment of brain tumours and
Menengeal leukaemiaMenengeal leukaemia. Nitrasoureas are. Nitrasoureas are
unstable structures that's whyunstable structures that's why
the drug decomposes spontaneously in the bodythe drug decomposes spontaneously in the body
to form 2 active compounds ----anto form 2 active compounds ----an
alkylating agent and a Carbamoylatingalkylating agent and a Carbamoylating
agent.agent.
The organic isocyanate which is formedThe organic isocyanate which is formed
carbamoylates lysine residues in proteinscarbamoylates lysine residues in proteins
and may inactive DNA repair enzymes.and may inactive DNA repair enzymes.
The alkylating agent reacts initially with theThe alkylating agent reacts initially with the O-6O-6
positionposition of a guanine moiety in one strand ofof a guanine moiety in one strand of
DNA, then with theDNA, then with the O-6 positionO-6 position of aof a
guanine unit or theguanine unit or the N-3 positionN-3 position of cytosineof cytosine
in the other strand to produce interstrandin the other strand to produce interstrand
cross-linking.cross-linking.
Mechanism: Carmustine creates
fragmented DNA, prevents DNA
synthesis via cross-linking of DNA, and
creates mutations in nucleotides.
Nitrosoureas have dual mechanisms of
Action where by they alkylate DNA and
Carbamoylate proteins.
Nitroso ureas decomposition to active electrophiles
(2-chloro ethyl carbocation)
(carbamylated Lys)
(BiCNU)
Synthesis of carmustineSynthesis of carmustine
(formic acid)
 Carmustine is a highly lipid-soluble nitrosurea compound. Carmustine, a
bifunctional alkylating agent, alkylates DNA and RNA, can cross-link DNA, and
inhibits several enzymes by carbamoylation
 Mechanism of actionMechanism of action: Carmustine causes cross-links in DNA: Carmustine causes cross-links in DNA
and RNA, leading to the inhibition of DNA synthesis, RNAand RNA, leading to the inhibition of DNA synthesis, RNA
production and RNA translation (protein synthesis).production and RNA translation (protein synthesis).
Carmustine also binds to and modifies (carbamoylates)Carmustine also binds to and modifies (carbamoylates)
glutathione reductase. This leads to cell death.glutathione reductase. This leads to cell death.
 uses of carmustine:
 *Brain tumours
 *Lymphoma, Hodgkin’s disease
 *Lymphoma, non-Hodgkin’s
 *Multiple myeloma
 *Melanoma
 *Gastrointestinal and lung cancer.

 Pharmacodynamics/KineticsPharmacodynamics/Kinetics
 Distribution: 3.3 L/kg; readily crosses blood-brain barrierDistribution: 3.3 L/kg; readily crosses blood-brain barrier
producing CSF levels equal to >50% of blood plasma levels;producing CSF levels equal to >50% of blood plasma levels;
highly lipid solublehighly lipid soluble
 Metabolism: Rapidly hepatic; forms active metabolitesMetabolism: Rapidly hepatic; forms active metabolites
 Half-life elimination: Biphasic: Initial: 1.4 minutes; Secondary:Half-life elimination: Biphasic: Initial: 1.4 minutes; Secondary:
20 minutes (active metabolites: plasma half-life of 67 hours)20 minutes (active metabolites: plasma half-life of 67 hours)
 Excretion: Urine (60% to 70%) within 96 hours; lungs (6% toExcretion: Urine (60% to 70%) within 96 hours; lungs (6% to
10% as CO2)10% as CO2)
 Physico-chemical propertiesPhysico-chemical properties::
white powder, slight odour. PH =5 to 6.0.white powder, slight odour. PH =5 to 6.0.
M.P=27-30M.P=27-3000
C, poorly soluble in water, freelyC, poorly soluble in water, freely
soluble in ethanolsoluble in ethanol..
Toxic effectsToxic effects: nausea, vomiting, abdominal pain,: nausea, vomiting, abdominal pain,
flushing, fever, chills, changes in visionflushing, fever, chills, changes in vision,,
Chest pain, yellowing of skin or eyes, headacheChest pain, yellowing of skin or eyes, headache..
Carmustine is given I.V because of its rapidCarmustine is given I.V because of its rapid
metabolized. Lomustine can be given orallymetabolized. Lomustine can be given orally..
ProcarbazineProcarbazine
 Procarbazine is an antineoplastic agent belonging to the class of alkylatingProcarbazine is an antineoplastic agent belonging to the class of alkylating
agent.agent.
 Chemically it is a derivative of methylhydrazine.Chemically it is a derivative of methylhydrazine.
Mechanism/mode of actionMechanism/mode of action ::
ProcarbazineProcarbazine exerts its cytotoxic action by Converting into highly reactiveexerts its cytotoxic action by Converting into highly reactive
alkylating speciesalkylating species azoprocarbazineazoprocarbazine which causeswhich causes 0066
-methylation-methylation ofof
guanine nucleotide pairs particularly with thymine.guanine nucleotide pairs particularly with thymine. This results inThis results in
mispairsmispairs thatthat Encourages point mutationsEncourages point mutations during replication cycles ofduring replication cycles of
DNA. Subsequently normal postreplicationDNA. Subsequently normal postreplication mis match Repair (MMR)mis match Repair (MMR)
systems gets activated and leads to the destruction of the cells.systems gets activated and leads to the destruction of the cells.
Physico-chemical propertiesPhysico-chemical properties::
Solid , slight odour,white to paleyellow colour, M.P= 2230
C Very soluble in water
Soluble in methanol and ethanol.
Adverse/toxic effects:
Nausea, vlomiting, constipation,drymouth,drowsiness,dizziness, muscle twitching,
Weakness and temporary hair loss. Severe chest pain, seizures,irregular heart bea
Mental changes, blood in urine or stools. Yellowing of eyes or skin.
Therapeutic
usesHodgkin’s lymphoma., It is also used for certain brain tumours, small-cell carcinomas
Of the lung, Non –Hodgkin’s lymphomas, and malignant melanoma.
Procarbazine metabolism and mechanism of action.
The methyl radical generator is utilized predominantly in the treatment of Hodgkin's disease.
It is administrered as capsules and is well absorbed after oral administration. It is metabolized in liver and
70% of administred dose is excreted in the urine as N-isopropylterephthalamic acid.
Facial flushing and other disulfiram-like symptoms are noted when alcohol is concomitantly consumed,
because the drug also inhibits enzymes involved in ethanol metabolism.
the methylating DNAquanine residues is proposed
to inhibit the de novo synthesis of proteins and
nuclic acids. procarbazine inhibits MAO,leading
several fatal drug-drug and drug-food interactions.
 Procarbazine is a prodrug and thought to undergo oxidation by cytochrome P450 enzymesProcarbazine is a prodrug and thought to undergo oxidation by cytochrome P450 enzymes
(ACTIVATED BY THE ENZYMES) to produce the methyl diazonium ion. This is alkylating(ACTIVATED BY THE ENZYMES) to produce the methyl diazonium ion. This is alkylating
agent . Reaction of this ion with RNA or DNA results in methylation mainly at the 0agent . Reaction of this ion with RNA or DNA results in methylation mainly at the 066
--
position of guanine. DNA fragmentation can also occur.position of guanine. DNA fragmentation can also occur.
N = N+
– CH3 ----------- N2 + +
CH3--
Synthesis
Methyl diazonium ion
condensation
Alkaline hydrolysis
ANTIMETABOLITESANTIMETABOLITES

Antimetabolites are agents whichAntimetabolites are agents which inhibit the enzymes involvedinhibit the enzymes involved
in the synthesis of DNA or its nucleotide building blocksin the synthesis of DNA or its nucleotide building blocks..
This is the another method of disrupting DNA function.This is the another method of disrupting DNA function.

TheThe inhibitorsinhibitors involved are described as antimetabolites.involved are described as antimetabolites.
Genarally the cellular components likeGenarally the cellular components like folic acid, purines andfolic acid, purines and
pyrimidinespyrimidines that are Involved in the synthesis of Nuclic acidsthat are Involved in the synthesis of Nuclic acids
(DNA,RNA)(DNA,RNA)
Antimetabolites inhibit nuclic acid synthesis by Competitive inhibitionAntimetabolites inhibit nuclic acid synthesis by Competitive inhibition
of cellular components.of cellular components.
They achieve this by combining with specific enzyme or gettingThey achieve this by combining with specific enzyme or getting
incorporated into the specific enzyme thereby forming inactiveincorporated into the specific enzyme thereby forming inactive
macromolecules and consequent cell death. They act specific phasemacromolecules and consequent cell death. They act specific phase
of the cell cycle.of the cell cycle.
5-fluorouracil :5-fluorouracil :Other Names: 5-FU, Adrucil®, Efudex
 It is an anticancer drug used for the treatment ofIt is an anticancer drug used for the treatment of
breast,liver, skin cancer which inhibit enzyme directly.breast,liver, skin cancer which inhibit enzyme directly.
 5-flurouracil is an antineoplastic agent belonging to the5-flurouracil is an antineoplastic agent belonging to the
class of antimetabolites i.e. pyrimidine antagonist.class of antimetabolites i.e. pyrimidine antagonist.
 It is a prodrug which is converted in theIt is a prodrug which is converted in the
body it its active form- deoxyribonucleotide that exertsbody it its active form- deoxyribonucleotide that exerts
the cytotoxic effect by inhibiting the normal pyrimidinethe cytotoxic effect by inhibiting the normal pyrimidine
formation which results in the inhibition of synthesis offormation which results in the inhibition of synthesis of
DNA.DNA.
mechanism of action of 5-fluorouracilmechanism of action of 5-fluorouracil
The mechanism of action of 5-fluorouracil (5-FU) has been associated with
inhibition of thymidylate synthase (TS) and incorporation of 5-FU into RNA
and DNA.
(deoxy thymidine monophosphate
5-fluorouraci is converted in the body to the flurinated analogure of 2’deoxyuridylic acid monophosphate which then converted
Combines with enzyme and
Cofactor to form a suicide substrate. up until this point nothing unusual has happened .
Tetrahydrofolate formed a covalent bond .
Proton lost from 5th
position
Here things start to
To go wrong further reaction
is impossible.
to the uracil via the methylene bridge. For this proton is required
Of uracil
Fluorine atom is there instead of hydrogen
As a result flurouracil skeleton remains covalently
Irreversibly bound to the active site. Now thymidine synthesis terminated.
metabolism of 5-fluorouracilmetabolism of 5-fluorouracil
Synthesis of 5-
flurouracil
It is a solid, white, odourless, partially soluble in water,methanol, insoluble in diehtyl
ether having melting point 282o
C.
Adverse /Toxic effects:
Therapeutic uses
5-Flurouracil is used for treating the following cancers
Breast cancer
Liver
Skin cancer
Stomach, pancreatic cancer, colon and rectal cancer.
Cancer of anus, bladder, cervix, endometrium, prostrate, ovaries, penis.
HN
N
H
O
O
CF3OF
Fluoroxy trifluoro methane
5-flurouracilUracil
HN
N
H
O
O
F
H
myelosuppression, mucositis, dermatitis, diarrhea and cardiac toxicity
6-Mercaptopurine.6-Mercaptopurine.6-Mercaptopurine is an anticancer drug6-Mercaptopurine is an anticancer drug
belonging to antimetabolite class.belonging to antimetabolite class.
Chemically it is a purine 6-thiol.Chemically it is a purine 6-thiol.
It is a purine analogue acts byIt is a purine analogue acts by inhibitinginhibiting
the metabolism of purinethe metabolism of purine which inturnwhich inturn
prevents the biosynthesis of normalprevents the biosynthesis of normal
cellular metabolism leading to cell death.cellular metabolism leading to cell death.
The drug also shows immunosuppressantThe drug also shows immunosuppressant
activity.activity.
Mechanism of actionMechanism of action
It is an analogue of naturally occurringIt is an analogue of naturally occurring
purine, which is essential component ofpurine, which is essential component of
DNA called adenine. After the intercellularDNA called adenine. After the intercellular
conversion of mecaptopurine to activeconversion of mecaptopurine to active
nucleosides, it gets interfered with nucleicnucleosides, it gets interfered with nucleic
acid synthesis.acid synthesis.
These are prodrugs which are converted toThese are prodrugs which are converted to
their corresponding nucleosidetheir corresponding nucleoside
monphosphates by cellular enzymes. Themonphosphates by cellular enzymes. The
monophosphates inhibit purine synthesismonophosphates inhibit purine synthesis
at a no. of points. They are alsoat a no. of points. They are also
incorporated into RNA and DNA, leadingincorporated into RNA and DNA, leading
to complex effects which end in cell death.to complex effects which end in cell death.
These agents are converted into to a commonThese agents are converted into to a common
product (thio-GMP) which is subsequentlyproduct (thio-GMP) which is subsequently
converted to thio -GTP and thio-dGTP,converted to thio -GTP and thio-dGTP,
before incorporation into RNA and DNAbefore incorporation into RNA and DNA
respecively.respecively.
Both these agents converts in to a common product
thio-GMP and next converts to thio- dGTP
before incorporation into
RNA and DNA
respectively.
 Mechanisms of actionMechanisms of action
 6-MP ribonucleotide inhibits purine6-MP ribonucleotide inhibits purine
nucleotide synthesis and metabolism. Thisnucleotide synthesis and metabolism. This
alters the synthesis and function ofalters the synthesis and function of RNARNA
andand DNADNA. Mercaptopurine interferes with. Mercaptopurine interferes with
nucleotidenucleotide interconversion andinterconversion and
glycoprotein synthesis.glycoprotein synthesis.
SynthesisSynthesis
Physico-chemical properties:
It is a yellow crystalline,odourless,tasteless powder and is insoluble in water,sligtly soluble
n ethanol, having M.P=3080
c. When exposed to air it gets darkened,therefore, it is
Stored in well closed containers.
Toxic effects/side effects/adverse effects:
Bone marrow depression,hyperuricaemia and reversible jaundice,nausea, vomting, anorexia,
Mouthsores.Rarely crystalluria with haematuria and skin reactions like hyperpigmentation
It is highly mutagenic and carcinogenic and and may increase in the risk of abortion when
Given to pregnant women.
Therapeutic uses:
It exhibits immunosuppressant action.
This drug is used in the primarily for the treatment of acute leukaemias and more effective
In children than adults.
Chorio carcinoma, chronic myelocytic leukeia, Non hodkin’s lymphoma, psoriatic arthritis,
Polycythemia vera, Ulcerative colitis and chrohn’s disease.
Dose: it is given orally at a dose of 2.5mg/kg body weight or 75 to 100 mg/sq.m BSA.
H
N
NN
N
OH
hypoxanthine
P2S5
Phosphorous pentasulphide
H
N
NN
N
SH
6-mercaptopurine
MethotrexateMethotrexate
Methotrexate is one of the most widely usedMethotrexate is one of the most widely used
Antimetabolites in cancer chemotherapy.Antimetabolites in cancer chemotherapy.
It is very similar structure to the natural folates differing only in additional amino and methyl groups.It is very similar structure to the natural folates differing only in additional amino and methyl groups.
It has a stronger binding affinity for the enzyme, due to an additional hydrogen bond or ionic bond which is not presentIt has a stronger binding affinity for the enzyme, due to an additional hydrogen bond or ionic bond which is not present
when FHwhen FH22 binds.binds.
AS a resut, methotrexate prevents the binding of FHAS a resut, methotrexate prevents the binding of FH22. As a result methotrexate prevents the binding of FH. As a result methotrexate prevents the binding of FH22 and itsand its
Conversion to NConversion to N55
,N,N1010
-methylene FH-methylene FH4.4.
Mechanism of action:Mechanism of action:
Methotrexate is an antagonist of folic acid.Methotrexate is an antagonist of folic acid.
The DHFR is an important enzyme required for the formation of THF from DHF.The DHFR is an important enzyme required for the formation of THF from DHF.
In the absence of THF, the cells cannot synthesize purine and thymidine nucleotides which ultimately blocks theIn the absence of THF, the cells cannot synthesize purine and thymidine nucleotides which ultimately blocks the
formation of DNA and RNA.formation of DNA and RNA.
Without DNA the cell cannot replicate and ultimately dies. The binding of methotrexate to DHFR is so tight that isWithout DNA the cell cannot replicate and ultimately dies. The binding of methotrexate to DHFR is so tight that is
termed as pseudoirreversible.termed as pseudoirreversible.
Dihydrofolate reductaseDihydrofolate reductase
Dihydrofolic acid ------------------------------------------Dihydrofolic acid ------------------------------------------ Tetrahydrofolic acid.Tetrahydrofolic acid.
Dihydrofolate reductaseDihydrofolate reductase
Methotrexate ----------------------------------------------Methotrexate ---------------------------------------------- No reaction.No reaction.
In the cell folic acid is first of all reduced to FHIn the cell folic acid is first of all reduced to FH22 and then FHand then FH4.4.
Methotrexate is able to inhibit the enzyme dihydrofolate reductase and does not allow the formation ofMethotrexate is able to inhibit the enzyme dihydrofolate reductase and does not allow the formation of
Tetrahydrofolate which has been essential for the synthesis of purine and pyrimidine and there by check theTetrahydrofolate which has been essential for the synthesis of purine and pyrimidine and there by check the
Formation of DNA and RNA.Formation of DNA and RNA.
Synthesis:
 Physico-chemical propertiesPhysico-chemical properties ::
It occurs as yellow to orange brown crystalline powder.It is insoluble in waterIt occurs as yellow to orange brown crystalline powder.It is insoluble in water
Freely soluble in dilute solution of alkali and slightly soluble in dil.Hcl .Freely soluble in dilute solution of alkali and slightly soluble in dil.Hcl .
M.P=192M.P=19200
c.c.
Adverse effectsAdverse effects ::
Depression of bone marrow which lead toDepression of bone marrow which lead to
Leucopenia,thrombocytopenia and anaemias.Leucopenia,thrombocytopenia and anaemias.
In low doses methotrexate is given repeatedly causes megaloblastic anaemiaIn low doses methotrexate is given repeatedly causes megaloblastic anaemia
and high doses produce pancytopenia.and high doses produce pancytopenia.
UsesUses::
It provedes great benefit to patients suffering withIt provedes great benefit to patients suffering with
Chronic carcinima, the acute leukemias,osteosarcoma, and head, neck andChronic carcinima, the acute leukemias,osteosarcoma, and head, neck and
breast cancer.breast cancer.
Lung cancer.Lung cancer.
Acute lymphocytic leukemia and acute myelocytic leukaemia.Acute lymphocytic leukemia and acute myelocytic leukaemia.
Poriasis.Poriasis.
Autoimmune diseases like dermatomyositis and rhuematoid arthritis.Autoimmune diseases like dermatomyositis and rhuematoid arthritis.
Dose: 30mg/sq.m BSA weekly in 2 divided doses for acute leukaemia.Dose: 30mg/sq.m BSA weekly in 2 divided doses for acute leukaemia.
For chronic carcinomas it is given as 15-30mg/day orally for 5 days.For chronic carcinomas it is given as 15-30mg/day orally for 5 days.
Vinka alkaloidsVinka alkaloids
Vinblastine is a clinically useful vinka alkaloid. It is derived form theVinblastine is a clinically useful vinka alkaloid. It is derived form the
Madagascar periwinkle plant(catharanthus roseus) formerly knownasMadagascar periwinkle plant(catharanthus roseus) formerly knownas VinkaVinka
rosea.rosea.
TThe alkaloidhe alkaloid vinblastine is made up of two Moieties namely catharanthinevinblastine is made up of two Moieties namely catharanthine
and vindolineand vindoline
Mechanism of actionMechanism of action::
Vinblastine shows its action by binding to tubulin to prevent it fromVinblastine shows its action by binding to tubulin to prevent it from
polymerizing into microtubules. Thus the drug prevents it polymerization inpolymerizing into microtubules. Thus the drug prevents it polymerization in
microtubules. This leads to inhibition of mitotic spindle formation bymicrotubules. This leads to inhibition of mitotic spindle formation by
arresting the mitosis at metaphase. Thus the cell division does not occur.arresting the mitosis at metaphase. Thus the cell division does not occur.
Physicochemical propertiesPhysicochemical properties::
It is white to slightly yellow crystalline odourless powder soluble in water,It is white to slightly yellow crystalline odourless powder soluble in water,
methanol, ethanol, chloroform and insoluble in ether having M.P=285methanol, ethanol, chloroform and insoluble in ether having M.P=285oo
C.C.
Toxic effectsToxic effects::
Nausea, vomiting and muscle plain, lower back pain, joint pain ,temporary hairNausea, vomiting and muscle plain, lower back pain, joint pain ,temporary hair
loss, painful urination, blood in urine or stools, dizziness, double vision mayloss, painful urination, blood in urine or stools, dizziness, double vision may
also occur, allergic reactions include rash, itching ,swelling and difficulty inalso occur, allergic reactions include rash, itching ,swelling and difficulty in
breathing.breathing.
Vincristine,Vinblastine,vinrosidine and vinleurosine are four closely relatedVincristine,Vinblastine,vinrosidine and vinleurosine are four closely related
compounds have antitumour activity.compounds have antitumour activity.
Semisynthetic derivative vinorelbine is also used as an antitumour agent.Semisynthetic derivative vinorelbine is also used as an antitumour agent.
Structure of vinblastineStructure of vinblastine
Chemically
it is a complex structure consisting of two polycyclic units i.e.
Catharathine and vindoline.
SARSAR::
The presence of acetyl group is very essential for vinblastine to exhibit it
Anti cancer activity. When this is hydrolysed activity gets destroyed.
2. When free hydroxyl grops were acetylated the drug lost its
Antimalignant activity.
3.The potency of vinblastine reduces drastically when the double bonds
Were initially hydrogenated and finally converted to carbinol group via
reduction.
Uses of vinblastine:Uses of vinblastine:
1.Vinblastine has been used in combination1.Vinblastine has been used in combination
Therapies for the treatment of lymphomas,Therapies for the treatment of lymphomas,
Testicular cancer and ovarian cancer.Testicular cancer and ovarian cancer.
Hodgkin’s disease.Hodgkin’s disease.
Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma
Kaposi’s sarcomaKaposi’s sarcoma
Mycosis fungoides.Mycosis fungoides.
DoseDose: It is administered 0.3mg/kg for 3 weeks by: It is administered 0.3mg/kg for 3 weeks by
I.V infusion.I.V infusion.
Vincristine:Vincristine:
Vincristine is also obtained from CatharanthusVincristine is also obtained from Catharanthus
roseus, (vinca rosea)roseus, (vinca rosea)
Chemically it consists of 2 polycyclic units.Chemically it consists of 2 polycyclic units.
It is made up of 2 moieties namely catharanthineIt is made up of 2 moieties namely catharanthine
and vindoline.and vindoline.
It binds to the tubulin and has greater affinityIt binds to the tubulin and has greater affinity
towards tubulin than the vinblastine.towards tubulin than the vinblastine.
It is mainly used in combination therapy to treatIt is mainly used in combination therapy to treat
Acute leukaemias, Hodgkin’s lymphoma, small cellAcute leukaemias, Hodgkin’s lymphoma, small cell
Lung carcinoma and a variety of other tumoues.Lung carcinoma and a variety of other tumoues.
Mechanisam of vincristine:Mechanisam of vincristine:
Tubulin is a structural protein which is crucial toTubulin is a structural protein which is crucial to
cell division.cell division.
Genarally when the cell is about to divide, itsGenarally when the cell is about to divide, its
Microtubules depolymerize to give tubulin.TheMicrotubules depolymerize to give tubulin.The
tubulin is then repolymerized to formtubulin is then repolymerized to form
Structure called a spindle which thenStructure called a spindle which then
serves to push apart the two new cells andserves to push apart the two new cells and
to act as a frame work on which theto act as a frame work on which the
chromosome of the original cell arechromosome of the original cell are
transferred to the nuclei of the daughtertransferred to the nuclei of the daughter
cells.cells.
Vincristine and vinblastine work by binding toVincristine and vinblastine work by binding to
tubulin to prevent thistubulin to prevent this
polymerization/depolymerization cycle takespolymerization/depolymerization cycle takes
Place, and thus inhibit the growth of tumours.Place, and thus inhibit the growth of tumours.
Physicochemical propertiesPhysicochemical properties::
It is white to yellow, crystalline,odourless,It is white to yellow, crystalline,odourless,
Freely soluble in water insoluble in ether and having M.P=22Freely soluble in water insoluble in ether and having M.P=2200
C.C.
Adverse effectsAdverse effects::
Loss of sleep, tendon reflexes, severe peripheral neuropathy, some time in severe casesLoss of sleep, tendon reflexes, severe peripheral neuropathy, some time in severe cases
loss of motor function, foot drop, ataxia, bone marrow suppression( it is less commonloss of motor function, foot drop, ataxia, bone marrow suppression( it is less common
than vinblastine), constipation, urinary disturbances and alopecia.than vinblastine), constipation, urinary disturbances and alopecia.
Vincristine is used combination therapy toVincristine is used combination therapy to
treat acute leukaemias, Hodgkin’s lymphoma, small cell lung cancer.treat acute leukaemias, Hodgkin’s lymphoma, small cell lung cancer.
Burkitt’s lymphomaBurkitt’s lymphoma
Wilm’s tumourWilm’s tumour
Myeloma and neuroblastomaMyeloma and neuroblastoma
Kaposi’s sarcomaKaposi’s sarcoma
RhabdomyosarcomaRhabdomyosarcoma
Brain, lung, breast and head and neck tumours.Brain, lung, breast and head and neck tumours.
Therapeutic uses:
 TheThe sulfur mustardssulfur mustards, of which, of which mustard gasmustard gas (1,5-(1,5-
dichloro-3-thiapentane) is a member, are a class ofdichloro-3-thiapentane) is a member, are a class of
relatedrelated cytotoxiccytotoxic,, vesicantvesicant chemical warfare agentschemical warfare agents withwith
the ability to form largethe ability to form large blistersblisters on exposed skin. Pureon exposed skin. Pure
sulfur mustards are colorless, viscous liquids at roomsulfur mustards are colorless, viscous liquids at room
temperature. However, when used in impure form astemperature. However, when used in impure form as
warfare agents they are usually yellow-brown in colorwarfare agents they are usually yellow-brown in color
and have an odor resemblingand have an odor resembling mustard plantsmustard plants,, garlicgarlic oror
horseradishhorseradish, hence the name Mustard agents can be, hence the name Mustard agents can be
deployed on the battlefield via spraying from aircraft, ordeployed on the battlefield via spraying from aircraft, or
more typically by means of air-dropped bombs ormore typically by means of air-dropped bombs or
artillery shellsartillery shells. It has proved effective against entrenched. It has proved effective against entrenched
troops and encampments. Without proper protection,troops and encampments. Without proper protection,
mustard gas can be proved to be lethal to infantrymustard gas can be proved to be lethal to infantry
Sulfur mustards and nitrogen mustardsSulfur mustards and nitrogen mustards
AA blister agentblister agent (also known as a(also known as a vesicantvesicant ) is a chemical compound that) is a chemical compound that
causes severe skin, eye and mucosal pain and irritation. They are named forcauses severe skin, eye and mucosal pain and irritation. They are named for
their ability to cause severetheir ability to cause severe chemical burnschemical burns, resulting in large, painful water, resulting in large, painful water
blistersblisters on the bodies of those affected. Although these compounds have beenon the bodies of those affected. Although these compounds have been
employed on occasion for medical purposes, their most common use is asemployed on occasion for medical purposes, their most common use is as
chemical warfare agentschemical warfare agents..
Most blister agents fall into one of three groups:Most blister agents fall into one of three groups:
Sulfur mustardsSulfur mustards – A family of– A family of sulfursulfur-based agents, including the so-called-based agents, including the so-called
"mustard gas"."mustard gas".
Nitrogen mustardsNitrogen mustards – A family of agents similar to the sulfur mustards, but– A family of agents similar to the sulfur mustards, but
based onbased on nitrogennitrogen instead of sulfurinstead of sulfur
Mechanism of toxicityMechanism of toxicity
The compound readily eliminates aThe compound readily eliminates a chloridechloride
ion by intramolecularion by intramolecular nucleophilic substitutionnucleophilic substitution
to form a cyclicto form a cyclic sulfoniumsulfonium ion. This veryion. This very
reactive intermediate tends to bond to thereactive intermediate tends to bond to the
guanineguanine nucleotidenucleotide inin DNADNA strands, which isstrands, which is
particularly detrimental to cellular health.Thisparticularly detrimental to cellular health.This
alkylation can lead toalkylation can lead to cellular deathcellular death andand
cancercancer .Mustard gas is not very soluble in.Mustard gas is not very soluble in
water but is very soluble in fat, contributing towater but is very soluble in fat, contributing to
its rapid absorption into the skinits rapid absorption into the skin
Antineoplastic agents(ravisankar)
Physiological effectsPhysiological effects
 Mustard gas has extremely powerfulMustard gas has extremely powerful vesicantvesicant effects on its victims. Additionally, it is stronglyeffects on its victims. Additionally, it is strongly
mutagenicmutagenic andand carcinogeniccarcinogenic, due to its alkylating properties. It is also, due to its alkylating properties. It is also lipophiliclipophilic. Because people. Because people
exposed to mustard gas rarely suffer immediate symptoms, and mustard-contaminated areasexposed to mustard gas rarely suffer immediate symptoms, and mustard-contaminated areas
may appear completely normal, victims can unknowingly receive high dosages. However, withinmay appear completely normal, victims can unknowingly receive high dosages. However, within
24 hours of exposure to mustard agent,24 hours of exposure to mustard agent, victims experience intense itching and skinvictims experience intense itching and skin
irritationirritation which gradually turns into large blisters filled with yellow fluid wherever the mustardwhich gradually turns into large blisters filled with yellow fluid wherever the mustard
agent contacted the skin. These areagent contacted the skin. These are chemical burnschemical burns and they are very debilitating. If the victim'sand they are very debilitating. If the victim's
eyes were exposed then they become sore, starting witheyes were exposed then they become sore, starting with conjunctivitisconjunctivitis,, after which the eyelidsafter which the eyelids
swell, resulting in temporaryswell, resulting in temporary blindnessblindness. According to the Medical Management of Chemical. According to the Medical Management of Chemical
Casualties handbook, there have been experimental cases in humans where the patient hasCasualties handbook, there have been experimental cases in humans where the patient has
sufferedsuffered miosismiosis, or pinpointing of pupils, as a result of the, or pinpointing of pupils, as a result of the cholinomimeticcholinomimetic activity of mustard.[activity of mustard.[
citation neededcitation needed] At very high concentrations, if inhaled, mustard agent causes bleeding and] At very high concentrations, if inhaled, mustard agent causes bleeding and
blistering within theblistering within the respiratory systemrespiratory system, damaging, damaging mucous membranesmucous membranes and causingand causing
pulmonary edemapulmonary edema. Depending on the level of contamination, mustard gas burns can vary. Depending on the level of contamination, mustard gas burns can vary
betweenbetween firstfirst andand second degree burnssecond degree burns , though they can also be every bit as severe,, though they can also be every bit as severe,
disfiguring and dangerous asdisfiguring and dangerous as third degree burnsthird degree burns[3][3]. Severe mustard gas burns (i.e. where more. Severe mustard gas burns (i.e. where more
than 50% of the victim's skin has been burned) are often fatal, with death occurring after somethan 50% of the victim's skin has been burned) are often fatal, with death occurring after some
days or even weeks have passed. Mild or moderate exposure to mustard agent is unlikely to kill,days or even weeks have passed. Mild or moderate exposure to mustard agent is unlikely to kill,
though victims invariably require lengthy periods of medical treatment andthough victims invariably require lengthy periods of medical treatment and convalescenceconvalescence beforebefore
recovery is complete. Therecovery is complete. The mutagenicmutagenic andand carcinogeniccarcinogenic effects of mustard agent mean thateffects of mustard agent mean that
victims who recover from mustard gas burns have an increased risk of developingvictims who recover from mustard gas burns have an increased risk of developing cancercancer in laterin later
life.life.
 Skin damage can be reduced ifSkin damage can be reduced if povidone-iodinepovidone-iodine in a base ofin a base of [1][1] is rapidly applied, but sinceis rapidly applied, but since
mustard agent initially has no symptoms, exposure is usually not recognised until skin irritationmustard agent initially has no symptoms, exposure is usually not recognised until skin irritation
begins—at which point it is too late for countermeasures. The vesicant property of mustard gasbegins—at which point it is too late for countermeasures. The vesicant property of mustard gas
can be neutralised bycan be neutralised by oxidationoxidation oror chlorinationchlorination; household bleach (; household bleach (sodium hypochloritesodium hypochlorite) or) or
decontamination solution "DS2" (2%decontamination solution "DS2" (2% NaOHNaOH, 70%, 70% diethylenetriaminediethylenetriamine, 28%, 28%
ethylene glycol monomethyl etherethylene glycol monomethyl ether) can be used. After initial decontamination of the victim's) can be used. After initial decontamination of the victim's
wounds is complete, medical treatment is similar to that required by any conventional burn. Thewounds is complete, medical treatment is similar to that required by any conventional burn. The
Soldier with muster gas burns to hisSoldier with muster gas burns to his
backback
Mustard gasMustard gas
 The most widely reported and, perhaps, the mostThe most widely reported and, perhaps, the most
effective gas of the First World War waseffective gas of the First World War was
mustard gasmustard gas, a, a vesicantvesicant, which was introduced by, which was introduced by
Germany in July 1917 prior to theGermany in July 1917 prior to the
Third Battle of YpresThird Battle of Ypres..[4][4] The Germans marked theirThe Germans marked their
shells yellow for mustard gas and green for chlorineshells yellow for mustard gas and green for chlorine
and phosgene, so they called the new gasand phosgene, so they called the new gas YellowYellow
CrossCross Mustard gas is not a particularly effectiveMustard gas is not a particularly effective
killing agent (though in high enough doses it iskilling agent (though in high enough doses it is
fatal) but can be used to harass and disable thefatal) but can be used to harass and disable the
enemy and pollute the battlefield. Delivered inenemy and pollute the battlefield. Delivered in
artillery shells, mustard gas was heavier than air,artillery shells, mustard gas was heavier than air,
and it settled to the ground as an oily liquidand it settled to the ground as an oily liquid
resemblingresembling sherrysherry. Once in the soil, mustard gas. Once in the soil, mustard gas
remained active for several days, weeks, or evenremained active for several days, weeks, or even
months, depending on the weather conditions.months, depending on the weather conditions.[32][32]
 The skin of victims of mustard gasThe skin of victims of mustard gas
blistered, their eyes became very sore andblistered, their eyes became very sore and
they began to vomit. Mustard gas causedthey began to vomit. Mustard gas caused
internal and external bleeding and attackedinternal and external bleeding and attacked
the bronchial tubesthe bronchial tubes , stripping off the mucous, stripping off the mucous
membrane. This was extremely painful and mostmembrane. This was extremely painful and most
soldiers had to be strapped to their beds. It usuallysoldiers had to be strapped to their beds. It usually
took a person four or five weeks to die of mustardtook a person four or five weeks to die of mustard
gas exposureMustard gas was the agent of choice,gas exposureMustard gas was the agent of choice,
with the British stockpiling 40,719 tons, thewith the British stockpiling 40,719 tons, the
Russians 77,400 tons, the Americans over 87,000Russians 77,400 tons, the Americans over 87,000
tons and the Germans 27,597 tons.tons and the Germans 27,597 tons.[38][38]
Antineoplastic agents(ravisankar)
Gases usedGases used
 A=Allies, C=Central PowersA=Allies, C=Central Powers NameFirst useTypeUsed byNameFirst useTypeUsed by
Xylyl bromideXylyl bromide[55][55]1914Lachrymatory, toxicBoth1914Lachrymatory, toxicBothChlorineChlorine[56][56]
1915Corrosive. Lung IrritantBoth1915Corrosive. Lung IrritantBothPhosgenePhosgene[56][56]1915Irritant - Skin and1915Irritant - Skin and
mucous membranes. Corrosive, toxicBothmucous membranes. Corrosive, toxicBothBenzyl bromideBenzyl bromide[55][55]
1915LachrymatoryC1915LachrymatoryCChloromethyl chloroformateChloromethyl chloroformate[55][55]1915Irritant - Eyes, skin,1915Irritant - Eyes, skin,
lungsBothlungsBothTrichloromethyl chloroformateTrichloromethyl chloroformate[55][55]1916Severe irritant, causes1916Severe irritant, causes
burnsBothburnsBothChloropicrinChloropicrin[56][56]1916Irritant, lachrymatory, toxicBoth1916Irritant, lachrymatory, toxicBoth
Stannic chlorideStannic chloride[55][55]1916Severe irritant, causes burnsAEthyl iodoacetate1916Severe irritant, causes burnsAEthyl iodoacetate[55][55]
1916Lachrymatory, toxicABromoacetone[55]1916Lachrymatory,1916Lachrymatory, toxicABromoacetone[55]1916Lachrymatory,
irritantBothMonobromomethyl ethyl ketone[55]1916Lachrymatory,irritantBothMonobromomethyl ethyl ketone[55]1916Lachrymatory,
irritantCAcrolein[55]1916Lachrymatory, toxicAHydrogen cyanide[55]irritantCAcrolein[55]1916Lachrymatory, toxicAHydrogen cyanide[55]
(Prussic acid)1916Toxic, Chemical AsphyxiantAHydrogen sulfide[55](Prussic acid)1916Toxic, Chemical AsphyxiantAHydrogen sulfide[55]
(Sulphuretted hydrogen)1916Irritant, toxicADiphenylchloroarsine[56](Sulphuretted hydrogen)1916Irritant, toxicADiphenylchloroarsine[56]
(Diphenyl chlorasine)1917Irritant/SternutatoryCa-Chlorotoluene (Benzyl(Diphenyl chlorasine)1917Irritant/SternutatoryCa-Chlorotoluene (Benzyl
chloride)1917Irritant, lachrymatoryCMustard gas[56] (Bis(2-chloroethyl)chloride)1917Irritant, lachrymatoryCMustard gas[56] (Bis(2-chloroethyl)
sulfide)1917Vesicant (blistering agent), lung irritantBothBis(chloromethyl)sulfide)1917Vesicant (blistering agent), lung irritantBothBis(chloromethyl)
ether (Dichloromethyl ether)1918Irritant, can blurether (Dichloromethyl ether)1918Irritant, can blur
visionCEthyldichloroarsine[56]1918VesicantCvisionCEthyldichloroarsine[56]1918VesicantCNN-Ethylcarbazole1918Irritant-Ethylcarbazole1918Irritant
Poison gas attack using gasPoison gas attack using gas
cylenders in world war -1cylenders in world war -1
ALTERNATIVES FORALTERNATIVES FOR
ANTINEOPLASTICSANTINEOPLASTICS
Cancer chemotherapy is now entering a new era which canCancer chemotherapy is now entering a new era which can
be described as molecular targeted therapeutics-highlybe described as molecular targeted therapeutics-highly
selective agents which target specific molecular targetsselective agents which target specific molecular targets
that are abnormal or over expressed in the cancer cell.that are abnormal or over expressed in the cancer cell.
Progress in this era has arisen from a better understandingProgress in this era has arisen from a better understanding
of the cellular chemistry involved in particular cancerof the cellular chemistry involved in particular cancer
cellscells
The development of kinase inhibitors such asThe development of kinase inhibitors such as
IMATINIB(glivec) is a much heralded illustration of thisIMATINIB(glivec) is a much heralded illustration of this
approachapproach
The use of antibodies and gene therapy is another area ofThe use of antibodies and gene therapy is another area of
research which shows huge potential.research which shows huge potential.
Finally, one of the best ways ofFinally, one of the best ways of
reducing cancer is …..reducing cancer is …..
 Firstly…Public education campaigns are important in highlighting the dangers ofFirstly…Public education campaigns are important in highlighting the dangers of
smoking, because possibly as many assmoking, because possibly as many as 30%30% of cancers are caused by smoking,of cancers are caused by smoking,
excessive drinking, and hazardous solvents, as well as promoting healthy diets andexcessive drinking, and hazardous solvents, as well as promoting healthy diets and
lifestyles.lifestyles.
 Secondly, anotherSecondly, another 30%30% of cancers are diet related that’s why everybody should takeof cancers are diet related that’s why everybody should take
healthy diets and lifestyles.healthy diets and lifestyles.
 The benefits of eating high-fibre foods, fruit, and vegetables are clear.The benefits of eating high-fibre foods, fruit, and vegetables are clear.
 Infact, there have been various research projects aimed at identifying the specificInfact, there have been various research projects aimed at identifying the specific
chemicals in these foods which are responsible for this protective property. Forchemicals in these foods which are responsible for this protective property. For
example,example,
 DithiolDithiolthiones are a group of chemicals inthiones are a group of chemicals in brobroccoccolili, cauliflower, and cabbage, cauliflower, and cabbage
which appear to have protective properties, one of which involves the activation ofwhich appear to have protective properties, one of which involves the activation of
enzymes in the liver to detoxify carcinogens.enzymes in the liver to detoxify carcinogens.
 GenisteinGenistein is a protective compound found inis a protective compound found in soy productssoy products used commonly inused commonly in
Asian populations have a low incidence of breast, prostate, colon cancers.Asian populations have a low incidence of breast, prostate, colon cancers.
 Epigallocatechin gallate, an antioxidant present inEpigallocatechin gallate, an antioxidant present in green teagreen tea, is another potential, is another potential
protective agent.protective agent.
 Synthetic drugs are also being investigated as possible cancer preventivesSynthetic drugs are also being investigated as possible cancer preventives
((finasfinasteride, aspirin, ibuprofen, andteride, aspirin, ibuprofen, and difluoromethyldifluoromethylornithine).ornithine).

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Antineoplastic agents(ravisankar)

  • 1. ANTINEOPLASTICANTINEOPLASTIC AGENTSAGENTS Dr. Ravisankar M. Pharm., PhD. Vignan pharmacy college , Vadlamudi-522 213, A.P., India.
  • 2. Introduction and HistoryIntroduction and History  The medical term for tumor (or) cancer isThe medical term for tumor (or) cancer is NeoplasmNeoplasm, Which means a relatively autonomous growth, Which means a relatively autonomous growth (or) uncorodinated cell proliferation of body tissue.(or) uncorodinated cell proliferation of body tissue.  The term Neoplasm meansThe term Neoplasm means New growthNew growth and theand the process of cell proliferation is calledprocess of cell proliferation is called NeoplasiaNeoplasia..  The branch of medicine which deals with theThe branch of medicine which deals with the excessive study of neoplasm (tumor) and itsexcessive study of neoplasm (tumor) and its development diagnosis and treatment is calleddevelopment diagnosis and treatment is called ““Oncology.Oncology.””  The term cancer was translated from aThe term cancer was translated from a Latin wordLatin word carcino i.e. Crabcarcino i.e. Crab by celsus.by celsus.  For the first time Hippocrates coined the Greek wordFor the first time Hippocrates coined the Greek word Karkinos i.e. (crab/cray fish)Karkinos i.e. (crab/cray fish) for malignant breast cancer.for malignant breast cancer.
  • 3. Classification of tumorsClassification of tumors  Tumor is general term for any abnormal mass orTumor is general term for any abnormal mass or growth of tissue which is not necessarily lifegrowth of tissue which is not necessarily life threatening, where as cancerous tumor is athreatening, where as cancerous tumor is a malignant neoplasm, which is highly dangerous.malignant neoplasm, which is highly dangerous.  Tumor is classified in toTumor is classified in to twotwo categories.categories. a.a. Malignant tumorMalignant tumor. (. (a disease or a growth that is likely to geta disease or a growth that is likely to get uncontrollably worse and lead to death)uncontrollably worse and lead to death) b.b. Non-Malignant tumorNon-Malignant tumor oror benignbenign tumor(tumor(a growtha growth that is not likely to cause death)that is not likely to cause death) or also known as non-or also known as non- cancerous tumor which does notcancerous tumor which does not metasmetastatasizesize..  MetasMetastata(i)(i) sis is secondary tumor or growthsis is secondary tumor or growth originating from the primary tumor and may groworiginating from the primary tumor and may grow elsewhere in the body.(elsewhere in the body.(If cancer cells metastasize, theyIf cancer cells metastasize, they spread to other parts of the body and cause tumours (= a mass of cells)spread to other parts of the body and cause tumours (= a mass of cells) to grow there.to grow there.
  • 4. Largest tumor ever removedLargest tumor ever removed According to Guinness WorldAccording to Guinness World Records, the biggest tumorRecords, the biggest tumor ever removed intact from theever removed intact from the human bodyhuman body weighed in atweighed in at 303 pounds303 pounds (137.6 kg)(137.6 kg) andand measuredmeasured 3 feet (1 m)3 feet (1 m) inin diameter.diameter.  The tumor, located on theThe tumor, located on the right ovaryright ovary, was removed in, was removed in 19911991 during an operationduring an operation performed by Professorperformed by Professor Katherine O’Hanlan atKatherine O’Hanlan at Stanford University MedicalStanford University Medical Center in CaliforniaCenter in California ..  The operation to remove theThe operation to remove the tumor from the abdomen oftumor from the abdomen of an unnamedan unnamed 34-year-old34-year-old womanwoman took overtook over six hourssix hours to complete.to complete.  TheThe pathologypathology reportreport concluded that the tumorconcluded that the tumor waswas benignbenign. The patient. The patient made a full recovery, andmade a full recovery, and reportedly did not seekreportedly did not seek treatment sooner due totreatment sooner due to being bed-ridden andbeing bed-ridden and suffering fromsuffering from agoraagoraphobiaphobia
  • 5. China’s elephant man grows world’s Largest tumor on face.(33 pounds) The man-with-no-face.
  • 6. Tumor growth and kineticsTumor growth and kinetics  The principle difference between mature of normal tissueThe principle difference between mature of normal tissue and tumors is …and tumors is …  The rate of cell replication i.e. proliferation for mostThe rate of cell replication i.e. proliferation for most normal tissues equals the rate of cell death (normal tissues equals the rate of cell death (a balance isa balance is maintained between cell renewal and cell apoptosismaintained between cell renewal and cell apoptosis (programmed cell death),(programmed cell death), where as in neoplasmwhere as in neoplasm proliferation exceeds the cell death.proliferation exceeds the cell death.  Proliferation in normal tissueProliferation in normal tissue responds to subtle signalsresponds to subtle signals that indicate when proliferation is needed repair,that indicate when proliferation is needed repair, regeneration or growth and developmentregeneration or growth and development. But .... But ...  Neoplasm seem toNeoplasm seem to lack such an auto regulationlack such an auto regulation ofof proliferation and the cell replication rate i.e. new cellsproliferation and the cell replication rate i.e. new cells replace the old cells by differentiation mechanism.replace the old cells by differentiation mechanism.
  • 7. Occasionally due to carcinogens (cancer causing agents) one of the Cell get mutated and does not respond to normal growth control mechanisms. This mutated cell undergoes further mutations and transforms i.e. to Converts in to tumor cell which starts proliferating vigorously. This in turn results in a mass of abnormal cells (tissues) called tumour or neoplasm.
  • 8. SIGNALS LEADING TO APOPTOSISSIGNALS LEADING TO APOPTOSIS cells no longer listen to the signals (In case of cancer cells)
  • 9. ANGIOGENISISANGIOGENISIS •Angiogenesis is the process by which tumours growth of new blood vessels to provide the nutrients required for continued growth. •As tumour grows, its cancerous cells Require a steady supply of amino acids, nucleic acid bases, carbohydrates, oxygen, And growth factors, if they are to continue multiplying. This means that the tumour has to have a good blood supply. • As a tumour grows in size, however, its cells become increasingly far away from the blood supply and become starved of these resources. This is particularly true for the cells in the centre of the tumour. •In order to counter This, tumour cells release growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF-2) which interact with receptors on the Endothelial cells of nearby blood vessels and stimulate these cells to divide, leading to the branching and extension of existing capillaries – a process known as angiogenesis. •Agents which inhibit angiogenisis( angiostatin and thrombospondin) are useful in anticancer therapy to inhibit growth and to enhance the effectiveness of other drugs. (If the cancer cells invade other parts Of body and set up secondary tumours — A process known as metastasis Newly developing Endothelial cells release protein release grwth factors As grows
  • 10. Genarally in all the organs and tissues of human beings a balance is maintained b/n cell renewal and cell apoptosis(programmed cell death). New cells replace the old cells by proliferation and differentiation mechanisms. Occasionally, due to carcinogens (cancer causing agents) one of the cells get mutated and does't respond to normal growth control mechanisms. This mutated cell undergoes further mutations and transforms in to tumour cell which starts poliferating vigorously. subsequently a mass of abnormal cells (tissues) called neoplasm or tumour. (vascular endothelial growth factor) one of the cell get mutated and FGF-2
  • 11. Doubling timeDoubling time The doubling time is theThe doubling time is the mean (“average”) interval betweenmean (“average”) interval between successive mitoses.successive mitoses.  It is a characteristic of the particular type of tumor cell. DoublingIt is a characteristic of the particular type of tumor cell. Doubling time varies markedly among various kinds of tumors.time varies markedly among various kinds of tumors.  Burkitt’s tumor = it is approximately 24hours.Burkitt’s tumor = it is approximately 24hours.  In acute leukemia = 2 weeks.In acute leukemia = 2 weeks.  In breast cancer = 3 months.In breast cancer = 3 months.  In multiple myeloma = 6 to 12 months.In multiple myeloma = 6 to 12 months.  Mucosal cells of the rectum every 24 hours.Mucosal cells of the rectum every 24 hours.  A tumor cell becomes detectable when the number of cells reachesA tumor cell becomes detectable when the number of cells reaches about 10about 1099 to 10to 101010 cells. This requirescells. This requires 30 to 3330 to 33 doubling times.doubling times.  The neoplasm becomes lethal when the population reaches aboutThe neoplasm becomes lethal when the population reaches about 5x105x101111 to 5x10to 5x101212 cells, aftercells, after 3939 toto 4242 doubling times.doubling times. Death mainly arises, due to the competition between normal and cancer cells for nutrition, blood supply etc as the cancer cells are rapidly dividing their number exceeds the normal cells and take away all the nutrients and make the normal cells to starve. As a result the normal cell functions are hindered and ultimately the organ becomes functionless, simply the cancer cells are parasites on normal cells. Moreover the cancer cells secrete no or more hormones that alters the homeostasis of the body.
  • 12.  CANCER STATISTICS.CANCER STATISTICS. According toAccording to World Cancer ReportWorld Cancer Report from the International Agency for Research onfrom the International Agency for Research on Cancer, cancer is projected to the leading cause of death in 2010. There were anCancer, cancer is projected to the leading cause of death in 2010. There were an estimated 12 million new cancer diagnoses and more than 7 million deaths worldwideestimated 12 million new cancer diagnoses and more than 7 million deaths worldwide this year. according to WHO “Cancer is a leading cause of death worldwide: itthis year. according to WHO “Cancer is a leading cause of death worldwide: it accounted for 7.4 million deaths (around 13% of all deaths) in 2004.”accounted for 7.4 million deaths (around 13% of all deaths) in 2004.”  lung (1.3 million deaths/year)lung (1.3 million deaths/year)  stomach (803 000 deaths)stomach (803 000 deaths)  colorectal (639 000 deaths)colorectal (639 000 deaths)  liver (610 000 deaths)liver (610 000 deaths)  breast (519 000 deaths).breast (519 000 deaths).  Among men - lung, stomach, liver, colorectal, oesophagus and prostateAmong men - lung, stomach, liver, colorectal, oesophagus and prostate  Among women - breast, lung, stomach, colorectal and cervicalAmong women - breast, lung, stomach, colorectal and cervical  IN INDIA 1 OUT OF 2 MENIN INDIA 1 OUT OF 2 MEN  1 OUT OF 3 WOMEN1 OUT OF 3 WOMEN  1 OUT OF 4 DEATHS IN THIS COUNTRY1 OUT OF 4 DEATHS IN THIS COUNTRY  is currently from cancer.is currently from cancer.
  • 13. CAUSES OF CANCERCAUSES OF CANCER  There are several agents responsible for cancer.There are several agents responsible for cancer. The agents (The agents (physical, chemical and biological)physical, chemical and biological) which causes cancer are calledwhich causes cancer are called carcinogenscarcinogens.. 1.1. Physical agentsPhysical agents: UV and ionizing radiations (x-ray, gamma and alpha and beta: UV and ionizing radiations (x-ray, gamma and alpha and beta rays cause cancer, uv rays of sunlight, nuclear fission. These radiations haverays cause cancer, uv rays of sunlight, nuclear fission. These radiations have mutagenic effect.mutagenic effect. Ex: Leukaemias, skin, lung, breast, osteosarcoma, thyroid cancer.Ex: Leukaemias, skin, lung, breast, osteosarcoma, thyroid cancer. 2.2. Biological agentsBiological agents:: a.a. Bacterial agentsBacterial agents: peptic ulcers and chronic gastritis and if these are left untreated: peptic ulcers and chronic gastritis and if these are left untreated for a long time leads to gastric cancer.for a long time leads to gastric cancer. b.b. Fungal agentsFungal agents: The fungus: The fungus Aspergillus flavusAspergillus flavus releasesreleases aflaaflatoxins in stored foodtoxins in stored food and grains. If this contaminated food is consumed (espicially by Hepatitis B virusand grains. If this contaminated food is consumed (espicially by Hepatitis B virus infected patients) it leads to hepatocellular carcinoma.infected patients) it leads to hepatocellular carcinoma. c.c. Viral agents:Viral agents: Cervical cancer, Burkitt’s lymphoma, hairy cell lukaemia, HaepaticCervical cancer, Burkitt’s lymphoma, hairy cell lukaemia, Haepatic carcinoma.carcinoma. 3.3. Chemical agentsChemical agents:: Alkylating agents, The acylating agents, PolyaromaticAlkylating agents, The acylating agents, Polyaromatic hydrocarbons, Aniline,hydrocarbons, Aniline, arsenic,anthracenes,dimethylsulphate,diepoxybutane,acetyl imidazole, dimethylarsenic,anthracenes,dimethylsulphate,diepoxybutane,acetyl imidazole, dimethyl carbamyl chloride.carbamyl chloride. 4.4. Genetic factorsGenetic factors:: Genetic inheritance plays a key role in causing some of theGenetic inheritance plays a key role in causing some of the cancers (breast carcinoma,retino blastinoma.cancers (breast carcinoma,retino blastinoma. 5.5. Diet and habitsDiet and habits: People taking rich in fats, low fibre content, stored grains.: People taking rich in fats, low fibre content, stored grains. Alcoholism, smoking, chewing tobacco and betel nut .Alcoholism, smoking, chewing tobacco and betel nut . 6.6. Hormones and DrugsHormones and Drugs: Taking excessive oestrogens during the times of: Taking excessive oestrogens during the times of pregancy(Vaginal endometrial cancer is prevalent in the girls born to the mothers)pregancy(Vaginal endometrial cancer is prevalent in the girls born to the mothers)
  • 14.  7.Epidemio7.Epidemiological factorslogical factors:: a.a. Geographical and Racial factorsGeographical and Racial factors:: Climate, soil, diet habit and customs etc. Genetic composition alsoClimate, soil, diet habit and customs etc. Genetic composition also influence the variations in cancer.influence the variations in cancer. Ex: Breast cancer in prevalent in American women.Ex: Breast cancer in prevalent in American women. Gastric carcinoma is in Japanese.Gastric carcinoma is in Japanese. b.b. Environmental and cultural factorsEnvironmental and cultural factors: Exposure to industrial: Exposure to industrial contaminants, smoke and radioactive metals.contaminants, smoke and radioactive metals. Cancer ofCancer of pepenisnis is very rare in Muslims and jews due to theis very rare in Muslims and jews due to the custom ofcustom of circumcircumcisioncision and their female partners are less likely toand their female partners are less likely to suffer(prone) to cancer of cervix.suffer(prone) to cancer of cervix. c.c. Age and sexAge and sex:: High risk of cancer is incident at an older age due toHigh risk of cancer is incident at an older age due to reduction in immunity. It is usually seen in 5reduction in immunity. It is usually seen in 5thth decade of life.decade of life. Men are more prone toMen are more prone to lung cancerlung cancer while women are susceptiblewhile women are susceptible toto breast cancerbreast cancer..
  • 15. ANTINEOPLASTIC AGENTSANTINEOPLASTIC AGENTS  Antineoplastic agents are the drugs which are used in toAntineoplastic agents are the drugs which are used in to management of malignant disease (i.e. cancer)management of malignant disease (i.e. cancer)  Antineoplastic agents are also known asAntineoplastic agents are also known as Cytotoxic agents.Cytotoxic agents. cancer is a very difficult disease to treat. This has been becausecancer is a very difficult disease to treat. This has been because ofof lack of reliable diagnostic tests for the early detectionlack of reliable diagnostic tests for the early detection andand notnot having the compounds which will cure any form of cancerhaving the compounds which will cure any form of cancer.. Anticancer drugs used in the treatment of malignant diseaseAnticancer drugs used in the treatment of malignant disease when surgery or radiotherapy is not possible or has provedwhen surgery or radiotherapy is not possible or has proved ineffective. They are also employed asineffective. They are also employed as adjunct to surgery or Radiotherapy. They are used asadjunct to surgery or Radiotherapy. They are used as the initial treatment as in laeukaemia.the initial treatment as in laeukaemia. Chemotherapy usually involves combinations of drugs havingChemotherapy usually involves combinations of drugs having different targets or mechanisms of action.Traditional anticancerdifferent targets or mechanisms of action.Traditional anticancer drugs are generally cytotoxic more modern drugs aredrugs are generally cytotoxic more modern drugs are selective in their action.selective in their action.
  • 16. TREATMENT OF CANCERTREATMENT OF CANCER  Cancer can be treated by the following means:Cancer can be treated by the following means:  1. Surgery1. Surgery  2. Radiation therapy2. Radiation therapy  3.Immunotherapy3.Immunotherapy  4.Hormonal therapy4.Hormonal therapy  5.Antibiotics5.Antibiotics  6.Chemotherapy6.Chemotherapy Chemotherapy is the term applied for a wide range of chemicalChemotherapy is the term applied for a wide range of chemical substances i.e. drugs that are employed in the treating the cancer.substances i.e. drugs that are employed in the treating the cancer. These drugs may act by various mechanisms likeThese drugs may act by various mechanisms like  Interfering with the replication of DNA.Interfering with the replication of DNA.  Inhibiting the formation of important molecules which areInhibiting the formation of important molecules which are needed for DNA formation.needed for DNA formation.  Inhibiting the mytotic spindle.Inhibiting the mytotic spindle.
  • 17. Infact, most of traditional Anticancer agentsInfact, most of traditional Anticancer agents now-a- days available which….now-a- days available which….  Increase survival time.Increase survival time.  Supress the growth of developing neoplasmSupress the growth of developing neoplasm  Sprerading of the disease from one place toSprerading of the disease from one place to another place.another place.  Relief of pain upto some extent.Relief of pain upto some extent.  Immunosuppressive agents are also used toImmunosuppressive agents are also used to prolong the life of organs and tissueprolong the life of organs and tissue transplants during surgical procedural methodstransplants during surgical procedural methods in cancer.in cancer.
  • 18. Classification of Antineoplastic drugsClassification of Antineoplastic drugs  Cytotoxic drugs:Cytotoxic drugs:  A.A. Alkylating agentsAlkylating agents :: 1.Mustard drugs:1.Mustard drugs: Mechlorethamine,Mechlorethamine, Chlorambucil,Chlorambucil, Cyclophosphomide, MelphalanCyclophosphomide, Melphalan .. 2.2. AziridinesAziridines :: Thiotepa.Thiotepa. 3.3. Alkyl sulphones:Alkyl sulphones: Busulphan.Busulphan. 4. Nitrosoureas :4. Nitrosoureas : Lomustine,(CeeNU)Lomustine,(CeeNU) CarmustineCarmustine.(BiCNU).(BiCNU) Procarbazine.Procarbazine. B.B. AntimetabolitesAntimetabolites :: Purie antagonists:Purie antagonists: 6-Mercaptopurine.6-Mercaptopurine. Folic acid antagonist:Folic acid antagonist: Methotrexate.Methotrexate. Pyrimidine antagonist:Pyrimidine antagonist: 5-Fluorouracil.5-Fluorouracil. C.C. Plant productsPlant products : 1. Vinka alkaloids.: 1. Vinka alkaloids. a.a. Vincristine b. VinblastineVincristine b. Vinblastine.. 2.Taxanes: Paclitaxel,2.Taxanes: Paclitaxel, DoceDocetaxel.taxel. D.D. AntibioticsAntibiotics: Dactinomycin, Daunorubicin, Doxorubicin, Mitomycin.: Dactinomycin, Daunorubicin, Doxorubicin, Mitomycin. E.E. RadioisotopesRadioisotopes: Radioiodine I: Radioiodine I131131 , Radiophosphorus P, Radiophosphorus P3232 ..
  • 19. Mechanism of actions of anticancer agentsMechanism of actions of anticancer agents
  • 20. Alkylating agentsAlkylating agents :: 1.Mustard drugs1.Mustard drugs : Mechlorethamine,: Mechlorethamine, Chlorambucil,Chlorambucil, Cyclophosphomide, MelphalanCyclophosphomide, Melphalan Nitrogen mustards get their name because they are related to the sulfur-containing Mustard gases used during First world War. The nitrogen mustard compound Chlormethine was the first alkylating agent to be used medicinally in 1942. If second alkyl halide is reacts with Water,but the crosslinking is major factor Chlormethine (Mechlorehtamine) is highly reactive To servive oral route and has to be Administered I.V. The side reaction can Be reduced by putting aromatic ring On the N atom instead of methyl group. The lone pair of nitrogen interacts with the pi system of the ring and Less available to displace the cl ion. As a result aziridinium ion less easily formed than only strong nucleophile guanine will react with it The melphalan takes this advantage of this property. cyclophosphomide LauncherCH3 Missile (odour resembling mustard,garlic plant hence the name given)
  • 21. Mechlorethamine(mustine,Nitrogenmustard)Mechlorethamine(mustine,Nitrogenmustard)  Metabolism:rapid hydrolysis by body fluids and demethylation in liverMetabolism:rapid hydrolysis by body fluids and demethylation in liver  active metabolite(s)yes; ethylenimonium derivative.active metabolite(s)yes; ethylenimonium derivative. MECHANISM OF ACTION: Mechlorethamine, a bifunctional alkylating agent, interferes with DNA replication and RNA transcription as the result of formation of unstable carbonium ions which form interstrand cross-links with DNA, likely binding at the N7 position of guanine. Mechlorethamine has weak immunosuppressive properties. Mechlorethamine is cell cycle phase-nonspecific; however, its effect is most pronounced in the S phase, and cell proliferation is arrested in the G2 phase. Topical activity of mechlorethamine may also involve immune mechanisms.
  • 22. Alkylating agents Contains ractive alkyl Groups. These compounds Produce highly reactive Carbonium ion intermeadiates Which form covalent bonds By alkylation with nucleophilic Groups react with the 7th Position of guanine in each of The double starnds of DNACausing croslinking/mispairing. This interferes in the separation of strands and prevents mitosis or arrest cell replication. Alkylating agents (DNA cross linging agents)Alkylating agents (DNA cross linging agents) Mechanism of actionMechanism of action Alkylation is defined as replacement of hydrogen on an atom by an alkyl group. nu - H + alkyl-Y ---------- alkyl – nu + H+ + Y - 7 7 DNA cross-linking agents such as nitrogen mustards are highly electrophillic (δ+ ) structures. When encountered the nucleophillic groups on various DNA bases(N7 of the guanine) readily attack the electrophilic drug, resulting in irreversible alkylation or complexation of the DNA base.
  • 23.  Mechanism of ActionMechanism of Action  Alkylating agents work by three different mechanisms: 1)Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in theattachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in theirDNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNAattempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA,synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA frombetween atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, andbeing separated for synthesis or transcription, and  3) the induction of mispairing of the nucleotides leading3) the induction of mispairing of the nucleotides leading to mutations.to mutations. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide.
  • 24. double stranded DNA has two strands A phosphate-deoxyribose polymer composes the backbone of the DNA adjacent sugars are connected by phosphodiester bonds nitrogenous bases are convalently bonded to the 1' carbon of the deoxyribose the two DNA strands are antiparallel the two strands are held together by hydrogen bonds between complementary bases adenine hydrogen bonds (base pairs) to thymine guanine hydrogen bonds to cytosine Components of DNA:
  • 25. Alkylation of DNA by the nitrogen mustard compound chlormethineAlkylation of DNA by the nitrogen mustard compound chlormethine Alkylating agents Contains reactive alkyl Groups .These compounds Produce highly reactive Carbonium ion intermeadiates Which form covalent bonds By alkylation with nucleophilic Groups react with the 7th Position of guanine in each of The double starnds of DNA Causing cross linking/mispairing. This interferes in the separation of strands and prevents mitosis or arrest cell replication Undergoes neibhobouring group reactions to form Stained 3 membered onium , ethylene imminium ion or Aziridinium ions, which react with guanine groups on DNA To produce cross-linking. If second alkyl halide reacts with Water Cross linking is the major factor carbocations are highly reactive (The 2 chlorine atoms are dramatically decrease the basic strength of amino N through strong electro -ve inductive effect.) un-ionized amine forms aziridinium ion. δ+
  • 26.  Structure activity relation ship:Structure activity relation ship: Cl-CH2-CH2-N-CH2-CH2-Cl R Bis-Beta haloalkylamine. The R group can be either alipatic or aromatic, is the main determinant of chemical reactivity oral bioavailability,and the nature and extent of side effects. Aliphatic nitorgen substituent(-CH3) will push electrons to the amine through sigma bonds. This electronic enrichment enhances the Nucleophilic character of the lone pair of electrons and increase the speed at which the β-carbon of the mustared will be attacked. whether the tumor cell or a healthy cell , the aziridinium ion as soon it forms will react with cell nucleophiles such as electron rich NH,OH, SH groups. The body water also can react with aziridinium ion. So intra and inter molicular reactions happens so rapidly almost no chance of exists for tissue or cell specificity. which means increased risk of serious side effects and toxicity. An aromatic N substituent (Phenyl)group conjugated with the mustard nitrogen will stabilize the lone pair of electrons through rosonance. It slows the intramolecular nucleophilic attack,aziridinium ion formation and DNA alkylation αβ α β (aromatic mustards have less side effects and oral administration) Ex:melphalan,chlorambucil. here attack of electrophilic beta corbon is very slow because formation of aziridinium ion also significantly delayed. DNA alkylation is controlled and the drug can be given orally. Nitrogen mustards can decompose in aqueous media through formation of the inactive dehalogenated diol. the oxygen of water can act as nucleophiles to advance this degradative process. so buffering solutions to a slightly acidic pH helps to enhance stability in aqueous solution.
  • 27. Some DNA alkylating agents such as nitrogen mustards and nitrosoureas are bifunctional meaning that one molecule of the drug can bind two distinct DNA bases and DNA cross-linking through two guanine N7 atoms results. Nitrogen mustards are bis(β-haloalkyl) amines. bis- means two; halo (short for halogen) here chlorine. The 2 chlorine atoms decreases the basic strength of the amino N through a strong inductive effect. The unionized amine (two lone pair of electrons) that allows the formation of the highly electrophilic aziridinium ion. Mechanism of action: The lone pair of electrons on the un-ionized amino group conducts an intramolecular nucleophilic attack at the β-carbon of the mustard, displacing chloride ion and forms highly reactive electrophilic aziridinium ion,a quaternary amine salt. The stained cyclic structure are highly electrophilic because of the strong -ve inductive effectve of the +ve charged N atom. DNA nucleophile conducts an intermolicular nucleophilic attack which breaks the aziridine ring and alkylates DNA. Here guanine is the nucleic acid base involved in the alkylation reaction. when aziridinium ring cleaves lone pair of electrons are regenerated on mustard nitrogen. In the same way second arm of the mustard and second molecule of DNA. Ultimately 2 molecules of DNA(guanine) will be cross-linked through the nitrogen mustard. mustard's drug hold covalently that's why unable to replicate DNA eventually cell death is invitable If this. is happening in a tumor cell, the therapeutic goal is accomplished. If this is happening in the healthy cell patient may experience side effects.
  • 28. ChlorambucilChlorambucil Solid, white, odourless, Insoluble in water, freely soluble in alcohol,acetone, Chloroform. M.P=64 to 66C. Physico - chemical properties Mechlorethamine is highly reactive and forms mono alkylation of DNA guanine units also possible. If second alkyl halide reacts With water, but the cross linking is major factor by which these drugs inhibit replication and acts as anticancer agents. This side reactions mentioned above can be reduced by lowering the reactivity of the alkylating agent by attaching Electron- withdrawing groups to the nitrogen to increase selectivity against DNA over proteins. Chlorambucil acts by cross linking of DNA which results in formation of altered proteins leading to decrease in cell division That ultimately causes death of the cell. Toxic effects: Anaemia,neutropenia,thrombocytopenia,nausia,vimiting,diarrhoea,appetite,sterility,confusion. Hallucinations . Skin reactions like rashes ,skin blistering and hepatotoxicity can also occur.
  • 29.  Mechanism of Action  Chlorambucil is an aromatic nitrogen mustard derivative which acts as a bifunctional alkylating agent.  Alkylation takes place through the formation of a highly reactive ethylenimonium radical. A probable mode of action involves cross-linkage of the ethylenimonium derivative between 2 strands of helical DNA and subsequent interference with replication  Metabolism  The metabolism of chlorambucil in man appears to be similar to that in laboratory animals and involves S-oxidation of the butyric acid side chain. Bis-2-chlorethyl-2(4- aminophenyl) acetic acid  [ phenylacetic acid mustard ( PAAM ) ] is a major metabolite of chorambucil. In a study of 12 patients   administered chlorambucil 0.2mg/kg bodyweight orally, the mean dose adjusted-peak plasma concentration of PAAM ( 306 + 73 ng/ml ) was reached within 1 – 3 hours. The mean terminal elimination plasma half-life was 1.8 + 0.4 hours. The significant contribution of PAAM to the alkylating activity of drug was evident as the mean area under the plasma concentration time curve (AUC) of PAAM was approximately 1.33 times greater than the AUC of chlorambucil. Phenyl acetic acid mustard (an active chlorambucil metabolite)
  • 30.  SAR of chlorambucil:SAR of chlorambucil: This aromatic ring is able to stabilize the lone pair of electrons on the mustard N through resonance with conjugated phenyl ring, slowing the formation of reactive aziridinium ion. Because the lone pair of electrons of clorambucil and other aromatic mustards is less reactive,there is a greater opportunity for distribution to cancer cells and a decreased incidence of severe side effects. This group (bis-β haloalkyl amine) is bifunctional (one molecule of the durg can bind tow distinct DNA bases) are very important for chemical reactivity of the drug.
  • 31.  LEUKERAN  Tablets  Chlorambucil Tablets 2mg and 5mg . Therapeutic Indications LEUKERAN is indicated in the treatment of:- • Hodgkin's disease • certain forms of non-Hodgkin's lymphoma • chronic lymphocytic leukaemia • Waldenstrom's macroglobulinaemia • Advanced ovarian adenocarcinoma Leukeran has a significant therapeutic effect on a proportion of patients with breast cancer. Multiple myeloma, Lymphosarcoma,Lymphocytic leukemia, Overian adenocarcinoma, testicular cancer.
  • 32. Busulphan(myleran)Busulphan(myleran) Busulphan is a cytotoxic drug belonging to the group of alklating agent. It Is chemically, busulfan is classified as an alkyl sulfonate. Mechanism of action: Busulphan is a bifunctional alkylating agent. In alkylation the sulphonate groups are good leaving groups and play a similar role to the Chlorines in the nitrogen mustards. The mechanism involves a direct SN2 Nucleophilic substitution of the sulfonate groups and does not involve an Intermediate similar to the aziridinium ion, The N-7 position of guanine residues is the most susceptible site for this reaction to form interstrand cross-linking. It Exerts its cytotoxic action by reacting with guanosine at N-7 position thereby Interfering with the replication of RNA as well. sulSulfonate groups are good leaving groups. Buslfan-mediated DNA alkylation: 7 7
  • 33.  Busulphan:  MECHANISM OF ACTION:  Busulfan is a bifunctional alkylating agent. Following systemic absorption, carbonium ions are rapidly formed, resulting in alkylation of DNA. This leads to breaks in the DNA molecule as well as cross-linking of the twin strands, resulting in interference of DNA replication and transcription of RNA. The antitumour activity of busulfan is cell cycle phase-nonspecific.  Metabolism: extensive hepatic metabolism, with CYP3A4 involvement; at least 12 metabolites identified with unknown activity  active metabolite(s) none known  inactive metabolite(s) 25-35% as methanesulfonic acid 
  • 34. Synthesis ofSynthesis of bubusulphansulphan Physico chemical properties: Solid, white, odourless,veryslightly soluble in water,alcohol,ether, and freely soluble in Acetone and chloroform. M.P =114 to 1180 c. Toxic effects: Serious bone marrow hypoplasia and myelosuppression are possibe with this agent,recovery from busulfan-induced panctopenia can take up to 2 years. Nausea , headache,constipation,flushing fever,irregular heart beat, Chest pain,blurred vision. Rashes ,iching,swelling and sterility can also occur. Therapeutic uses: 1.It is used in the treatment of chronic granulocytic leukemia and may increase the life expectancy of patients by about a year. 2. Chronic Myelogenous leukemia. 3. Disorders of bone marrow like severy thrombocytosis, myelofibrosis, polycythemia vera. Dose: orally 0.3mg/kg to a maximum of 4mg/kg daily. (or) by IV infusion.
  • 35. CARMUSTINECARMUSTINE Brand name (BiCNU):Brand name (BiCNU):  BiCNU® (carmustine) is one of the nitrosoureas used in the treatment ofBiCNU® (carmustine) is one of the nitrosoureas used in the treatment of certain neoplastic diseases.certain neoplastic diseases.  It is 1,3-bis (2-chloroethyl)-1-nitrosourea.It is 1,3-bis (2-chloroethyl)-1-nitrosourea.  It is lyophilized pale yellow flakes or congealed mass with a molecularIt is lyophilized pale yellow flakes or congealed mass with a molecular weight of 214.06.weight of 214.06.  It is highly soluble in alcohol and lipids, and poorly soluble in water.It is highly soluble in alcohol and lipids, and poorly soluble in water.  BiCNU is administered by intravenous infusion after reconstitution asBiCNU is administered by intravenous infusion after reconstitution as recommended.recommended. 1,3-bis (2-chloroethyl)-1-nitrosourea.1,3-bis (2-chloroethyl)-1-nitrosourea. ( BiCNU)Iupac name: 1 32
  • 36. Nitrasoureas:Nitrasoureas: CarmustineCarmustine Carmustine and lomustine are examples ofCarmustine and lomustine are examples of chloroethylnitrasoureaschloroethylnitrasoureas Which are lipid soluble and can cross the blood-Which are lipid soluble and can cross the blood- brain barrier. As a result they have beenbrain barrier. As a result they have been used in the treatment of brain tumours andused in the treatment of brain tumours and Menengeal leukaemiaMenengeal leukaemia. Nitrasoureas are. Nitrasoureas are unstable structures that's whyunstable structures that's why the drug decomposes spontaneously in the bodythe drug decomposes spontaneously in the body to form 2 active compounds ----anto form 2 active compounds ----an alkylating agent and a Carbamoylatingalkylating agent and a Carbamoylating agent.agent. The organic isocyanate which is formedThe organic isocyanate which is formed carbamoylates lysine residues in proteinscarbamoylates lysine residues in proteins and may inactive DNA repair enzymes.and may inactive DNA repair enzymes. The alkylating agent reacts initially with theThe alkylating agent reacts initially with the O-6O-6 positionposition of a guanine moiety in one strand ofof a guanine moiety in one strand of DNA, then with theDNA, then with the O-6 positionO-6 position of aof a guanine unit or theguanine unit or the N-3 positionN-3 position of cytosineof cytosine in the other strand to produce interstrandin the other strand to produce interstrand cross-linking.cross-linking. Mechanism: Carmustine creates fragmented DNA, prevents DNA synthesis via cross-linking of DNA, and creates mutations in nucleotides. Nitrosoureas have dual mechanisms of Action where by they alkylate DNA and Carbamoylate proteins. Nitroso ureas decomposition to active electrophiles (2-chloro ethyl carbocation) (carbamylated Lys) (BiCNU)
  • 37. Synthesis of carmustineSynthesis of carmustine (formic acid)
  • 38.  Carmustine is a highly lipid-soluble nitrosurea compound. Carmustine, a bifunctional alkylating agent, alkylates DNA and RNA, can cross-link DNA, and inhibits several enzymes by carbamoylation  Mechanism of actionMechanism of action: Carmustine causes cross-links in DNA: Carmustine causes cross-links in DNA and RNA, leading to the inhibition of DNA synthesis, RNAand RNA, leading to the inhibition of DNA synthesis, RNA production and RNA translation (protein synthesis).production and RNA translation (protein synthesis). Carmustine also binds to and modifies (carbamoylates)Carmustine also binds to and modifies (carbamoylates) glutathione reductase. This leads to cell death.glutathione reductase. This leads to cell death.  uses of carmustine:  *Brain tumours  *Lymphoma, Hodgkin’s disease  *Lymphoma, non-Hodgkin’s  *Multiple myeloma  *Melanoma  *Gastrointestinal and lung cancer. 
  • 39.  Pharmacodynamics/KineticsPharmacodynamics/Kinetics  Distribution: 3.3 L/kg; readily crosses blood-brain barrierDistribution: 3.3 L/kg; readily crosses blood-brain barrier producing CSF levels equal to >50% of blood plasma levels;producing CSF levels equal to >50% of blood plasma levels; highly lipid solublehighly lipid soluble  Metabolism: Rapidly hepatic; forms active metabolitesMetabolism: Rapidly hepatic; forms active metabolites  Half-life elimination: Biphasic: Initial: 1.4 minutes; Secondary:Half-life elimination: Biphasic: Initial: 1.4 minutes; Secondary: 20 minutes (active metabolites: plasma half-life of 67 hours)20 minutes (active metabolites: plasma half-life of 67 hours)  Excretion: Urine (60% to 70%) within 96 hours; lungs (6% toExcretion: Urine (60% to 70%) within 96 hours; lungs (6% to 10% as CO2)10% as CO2)
  • 40.  Physico-chemical propertiesPhysico-chemical properties:: white powder, slight odour. PH =5 to 6.0.white powder, slight odour. PH =5 to 6.0. M.P=27-30M.P=27-3000 C, poorly soluble in water, freelyC, poorly soluble in water, freely soluble in ethanolsoluble in ethanol.. Toxic effectsToxic effects: nausea, vomiting, abdominal pain,: nausea, vomiting, abdominal pain, flushing, fever, chills, changes in visionflushing, fever, chills, changes in vision,, Chest pain, yellowing of skin or eyes, headacheChest pain, yellowing of skin or eyes, headache.. Carmustine is given I.V because of its rapidCarmustine is given I.V because of its rapid metabolized. Lomustine can be given orallymetabolized. Lomustine can be given orally..
  • 41. ProcarbazineProcarbazine  Procarbazine is an antineoplastic agent belonging to the class of alkylatingProcarbazine is an antineoplastic agent belonging to the class of alkylating agent.agent.  Chemically it is a derivative of methylhydrazine.Chemically it is a derivative of methylhydrazine. Mechanism/mode of actionMechanism/mode of action :: ProcarbazineProcarbazine exerts its cytotoxic action by Converting into highly reactiveexerts its cytotoxic action by Converting into highly reactive alkylating speciesalkylating species azoprocarbazineazoprocarbazine which causeswhich causes 0066 -methylation-methylation ofof guanine nucleotide pairs particularly with thymine.guanine nucleotide pairs particularly with thymine. This results inThis results in mispairsmispairs thatthat Encourages point mutationsEncourages point mutations during replication cycles ofduring replication cycles of DNA. Subsequently normal postreplicationDNA. Subsequently normal postreplication mis match Repair (MMR)mis match Repair (MMR) systems gets activated and leads to the destruction of the cells.systems gets activated and leads to the destruction of the cells. Physico-chemical propertiesPhysico-chemical properties:: Solid , slight odour,white to paleyellow colour, M.P= 2230 C Very soluble in water Soluble in methanol and ethanol. Adverse/toxic effects: Nausea, vlomiting, constipation,drymouth,drowsiness,dizziness, muscle twitching, Weakness and temporary hair loss. Severe chest pain, seizures,irregular heart bea Mental changes, blood in urine or stools. Yellowing of eyes or skin. Therapeutic usesHodgkin’s lymphoma., It is also used for certain brain tumours, small-cell carcinomas Of the lung, Non –Hodgkin’s lymphomas, and malignant melanoma.
  • 42. Procarbazine metabolism and mechanism of action. The methyl radical generator is utilized predominantly in the treatment of Hodgkin's disease. It is administrered as capsules and is well absorbed after oral administration. It is metabolized in liver and 70% of administred dose is excreted in the urine as N-isopropylterephthalamic acid. Facial flushing and other disulfiram-like symptoms are noted when alcohol is concomitantly consumed, because the drug also inhibits enzymes involved in ethanol metabolism. the methylating DNAquanine residues is proposed to inhibit the de novo synthesis of proteins and nuclic acids. procarbazine inhibits MAO,leading several fatal drug-drug and drug-food interactions.
  • 43.  Procarbazine is a prodrug and thought to undergo oxidation by cytochrome P450 enzymesProcarbazine is a prodrug and thought to undergo oxidation by cytochrome P450 enzymes (ACTIVATED BY THE ENZYMES) to produce the methyl diazonium ion. This is alkylating(ACTIVATED BY THE ENZYMES) to produce the methyl diazonium ion. This is alkylating agent . Reaction of this ion with RNA or DNA results in methylation mainly at the 0agent . Reaction of this ion with RNA or DNA results in methylation mainly at the 066 -- position of guanine. DNA fragmentation can also occur.position of guanine. DNA fragmentation can also occur. N = N+ – CH3 ----------- N2 + + CH3-- Synthesis Methyl diazonium ion condensation Alkaline hydrolysis
  • 44. ANTIMETABOLITESANTIMETABOLITES  Antimetabolites are agents whichAntimetabolites are agents which inhibit the enzymes involvedinhibit the enzymes involved in the synthesis of DNA or its nucleotide building blocksin the synthesis of DNA or its nucleotide building blocks.. This is the another method of disrupting DNA function.This is the another method of disrupting DNA function.  TheThe inhibitorsinhibitors involved are described as antimetabolites.involved are described as antimetabolites. Genarally the cellular components likeGenarally the cellular components like folic acid, purines andfolic acid, purines and pyrimidinespyrimidines that are Involved in the synthesis of Nuclic acidsthat are Involved in the synthesis of Nuclic acids (DNA,RNA)(DNA,RNA) Antimetabolites inhibit nuclic acid synthesis by Competitive inhibitionAntimetabolites inhibit nuclic acid synthesis by Competitive inhibition of cellular components.of cellular components. They achieve this by combining with specific enzyme or gettingThey achieve this by combining with specific enzyme or getting incorporated into the specific enzyme thereby forming inactiveincorporated into the specific enzyme thereby forming inactive macromolecules and consequent cell death. They act specific phasemacromolecules and consequent cell death. They act specific phase of the cell cycle.of the cell cycle.
  • 45. 5-fluorouracil :5-fluorouracil :Other Names: 5-FU, Adrucil®, Efudex  It is an anticancer drug used for the treatment ofIt is an anticancer drug used for the treatment of breast,liver, skin cancer which inhibit enzyme directly.breast,liver, skin cancer which inhibit enzyme directly.  5-flurouracil is an antineoplastic agent belonging to the5-flurouracil is an antineoplastic agent belonging to the class of antimetabolites i.e. pyrimidine antagonist.class of antimetabolites i.e. pyrimidine antagonist.  It is a prodrug which is converted in theIt is a prodrug which is converted in the body it its active form- deoxyribonucleotide that exertsbody it its active form- deoxyribonucleotide that exerts the cytotoxic effect by inhibiting the normal pyrimidinethe cytotoxic effect by inhibiting the normal pyrimidine formation which results in the inhibition of synthesis offormation which results in the inhibition of synthesis of DNA.DNA.
  • 46. mechanism of action of 5-fluorouracilmechanism of action of 5-fluorouracil The mechanism of action of 5-fluorouracil (5-FU) has been associated with inhibition of thymidylate synthase (TS) and incorporation of 5-FU into RNA and DNA.
  • 47. (deoxy thymidine monophosphate 5-fluorouraci is converted in the body to the flurinated analogure of 2’deoxyuridylic acid monophosphate which then converted Combines with enzyme and Cofactor to form a suicide substrate. up until this point nothing unusual has happened . Tetrahydrofolate formed a covalent bond . Proton lost from 5th position Here things start to To go wrong further reaction is impossible. to the uracil via the methylene bridge. For this proton is required Of uracil Fluorine atom is there instead of hydrogen As a result flurouracil skeleton remains covalently Irreversibly bound to the active site. Now thymidine synthesis terminated.
  • 49. Synthesis of 5- flurouracil It is a solid, white, odourless, partially soluble in water,methanol, insoluble in diehtyl ether having melting point 282o C. Adverse /Toxic effects: Therapeutic uses 5-Flurouracil is used for treating the following cancers Breast cancer Liver Skin cancer Stomach, pancreatic cancer, colon and rectal cancer. Cancer of anus, bladder, cervix, endometrium, prostrate, ovaries, penis. HN N H O O CF3OF Fluoroxy trifluoro methane 5-flurouracilUracil HN N H O O F H myelosuppression, mucositis, dermatitis, diarrhea and cardiac toxicity
  • 50. 6-Mercaptopurine.6-Mercaptopurine.6-Mercaptopurine is an anticancer drug6-Mercaptopurine is an anticancer drug belonging to antimetabolite class.belonging to antimetabolite class. Chemically it is a purine 6-thiol.Chemically it is a purine 6-thiol. It is a purine analogue acts byIt is a purine analogue acts by inhibitinginhibiting the metabolism of purinethe metabolism of purine which inturnwhich inturn prevents the biosynthesis of normalprevents the biosynthesis of normal cellular metabolism leading to cell death.cellular metabolism leading to cell death. The drug also shows immunosuppressantThe drug also shows immunosuppressant activity.activity. Mechanism of actionMechanism of action It is an analogue of naturally occurringIt is an analogue of naturally occurring purine, which is essential component ofpurine, which is essential component of DNA called adenine. After the intercellularDNA called adenine. After the intercellular conversion of mecaptopurine to activeconversion of mecaptopurine to active nucleosides, it gets interfered with nucleicnucleosides, it gets interfered with nucleic acid synthesis.acid synthesis. These are prodrugs which are converted toThese are prodrugs which are converted to their corresponding nucleosidetheir corresponding nucleoside monphosphates by cellular enzymes. Themonphosphates by cellular enzymes. The monophosphates inhibit purine synthesismonophosphates inhibit purine synthesis at a no. of points. They are alsoat a no. of points. They are also incorporated into RNA and DNA, leadingincorporated into RNA and DNA, leading to complex effects which end in cell death.to complex effects which end in cell death. These agents are converted into to a commonThese agents are converted into to a common product (thio-GMP) which is subsequentlyproduct (thio-GMP) which is subsequently converted to thio -GTP and thio-dGTP,converted to thio -GTP and thio-dGTP, before incorporation into RNA and DNAbefore incorporation into RNA and DNA respecively.respecively. Both these agents converts in to a common product thio-GMP and next converts to thio- dGTP before incorporation into RNA and DNA respectively.
  • 51.  Mechanisms of actionMechanisms of action  6-MP ribonucleotide inhibits purine6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism. Thisnucleotide synthesis and metabolism. This alters the synthesis and function ofalters the synthesis and function of RNARNA andand DNADNA. Mercaptopurine interferes with. Mercaptopurine interferes with nucleotidenucleotide interconversion andinterconversion and glycoprotein synthesis.glycoprotein synthesis.
  • 52. SynthesisSynthesis Physico-chemical properties: It is a yellow crystalline,odourless,tasteless powder and is insoluble in water,sligtly soluble n ethanol, having M.P=3080 c. When exposed to air it gets darkened,therefore, it is Stored in well closed containers. Toxic effects/side effects/adverse effects: Bone marrow depression,hyperuricaemia and reversible jaundice,nausea, vomting, anorexia, Mouthsores.Rarely crystalluria with haematuria and skin reactions like hyperpigmentation It is highly mutagenic and carcinogenic and and may increase in the risk of abortion when Given to pregnant women. Therapeutic uses: It exhibits immunosuppressant action. This drug is used in the primarily for the treatment of acute leukaemias and more effective In children than adults. Chorio carcinoma, chronic myelocytic leukeia, Non hodkin’s lymphoma, psoriatic arthritis, Polycythemia vera, Ulcerative colitis and chrohn’s disease. Dose: it is given orally at a dose of 2.5mg/kg body weight or 75 to 100 mg/sq.m BSA. H N NN N OH hypoxanthine P2S5 Phosphorous pentasulphide H N NN N SH 6-mercaptopurine
  • 53. MethotrexateMethotrexate Methotrexate is one of the most widely usedMethotrexate is one of the most widely used Antimetabolites in cancer chemotherapy.Antimetabolites in cancer chemotherapy. It is very similar structure to the natural folates differing only in additional amino and methyl groups.It is very similar structure to the natural folates differing only in additional amino and methyl groups. It has a stronger binding affinity for the enzyme, due to an additional hydrogen bond or ionic bond which is not presentIt has a stronger binding affinity for the enzyme, due to an additional hydrogen bond or ionic bond which is not present when FHwhen FH22 binds.binds. AS a resut, methotrexate prevents the binding of FHAS a resut, methotrexate prevents the binding of FH22. As a result methotrexate prevents the binding of FH. As a result methotrexate prevents the binding of FH22 and itsand its Conversion to NConversion to N55 ,N,N1010 -methylene FH-methylene FH4.4. Mechanism of action:Mechanism of action: Methotrexate is an antagonist of folic acid.Methotrexate is an antagonist of folic acid. The DHFR is an important enzyme required for the formation of THF from DHF.The DHFR is an important enzyme required for the formation of THF from DHF. In the absence of THF, the cells cannot synthesize purine and thymidine nucleotides which ultimately blocks theIn the absence of THF, the cells cannot synthesize purine and thymidine nucleotides which ultimately blocks the formation of DNA and RNA.formation of DNA and RNA. Without DNA the cell cannot replicate and ultimately dies. The binding of methotrexate to DHFR is so tight that isWithout DNA the cell cannot replicate and ultimately dies. The binding of methotrexate to DHFR is so tight that is termed as pseudoirreversible.termed as pseudoirreversible. Dihydrofolate reductaseDihydrofolate reductase Dihydrofolic acid ------------------------------------------Dihydrofolic acid ------------------------------------------ Tetrahydrofolic acid.Tetrahydrofolic acid. Dihydrofolate reductaseDihydrofolate reductase Methotrexate ----------------------------------------------Methotrexate ---------------------------------------------- No reaction.No reaction. In the cell folic acid is first of all reduced to FHIn the cell folic acid is first of all reduced to FH22 and then FHand then FH4.4. Methotrexate is able to inhibit the enzyme dihydrofolate reductase and does not allow the formation ofMethotrexate is able to inhibit the enzyme dihydrofolate reductase and does not allow the formation of Tetrahydrofolate which has been essential for the synthesis of purine and pyrimidine and there by check theTetrahydrofolate which has been essential for the synthesis of purine and pyrimidine and there by check the Formation of DNA and RNA.Formation of DNA and RNA.
  • 55.  Physico-chemical propertiesPhysico-chemical properties :: It occurs as yellow to orange brown crystalline powder.It is insoluble in waterIt occurs as yellow to orange brown crystalline powder.It is insoluble in water Freely soluble in dilute solution of alkali and slightly soluble in dil.Hcl .Freely soluble in dilute solution of alkali and slightly soluble in dil.Hcl . M.P=192M.P=19200 c.c. Adverse effectsAdverse effects :: Depression of bone marrow which lead toDepression of bone marrow which lead to Leucopenia,thrombocytopenia and anaemias.Leucopenia,thrombocytopenia and anaemias. In low doses methotrexate is given repeatedly causes megaloblastic anaemiaIn low doses methotrexate is given repeatedly causes megaloblastic anaemia and high doses produce pancytopenia.and high doses produce pancytopenia. UsesUses:: It provedes great benefit to patients suffering withIt provedes great benefit to patients suffering with Chronic carcinima, the acute leukemias,osteosarcoma, and head, neck andChronic carcinima, the acute leukemias,osteosarcoma, and head, neck and breast cancer.breast cancer. Lung cancer.Lung cancer. Acute lymphocytic leukemia and acute myelocytic leukaemia.Acute lymphocytic leukemia and acute myelocytic leukaemia. Poriasis.Poriasis. Autoimmune diseases like dermatomyositis and rhuematoid arthritis.Autoimmune diseases like dermatomyositis and rhuematoid arthritis. Dose: 30mg/sq.m BSA weekly in 2 divided doses for acute leukaemia.Dose: 30mg/sq.m BSA weekly in 2 divided doses for acute leukaemia. For chronic carcinomas it is given as 15-30mg/day orally for 5 days.For chronic carcinomas it is given as 15-30mg/day orally for 5 days.
  • 56. Vinka alkaloidsVinka alkaloids Vinblastine is a clinically useful vinka alkaloid. It is derived form theVinblastine is a clinically useful vinka alkaloid. It is derived form the Madagascar periwinkle plant(catharanthus roseus) formerly knownasMadagascar periwinkle plant(catharanthus roseus) formerly knownas VinkaVinka rosea.rosea. TThe alkaloidhe alkaloid vinblastine is made up of two Moieties namely catharanthinevinblastine is made up of two Moieties namely catharanthine and vindolineand vindoline Mechanism of actionMechanism of action:: Vinblastine shows its action by binding to tubulin to prevent it fromVinblastine shows its action by binding to tubulin to prevent it from polymerizing into microtubules. Thus the drug prevents it polymerization inpolymerizing into microtubules. Thus the drug prevents it polymerization in microtubules. This leads to inhibition of mitotic spindle formation bymicrotubules. This leads to inhibition of mitotic spindle formation by arresting the mitosis at metaphase. Thus the cell division does not occur.arresting the mitosis at metaphase. Thus the cell division does not occur. Physicochemical propertiesPhysicochemical properties:: It is white to slightly yellow crystalline odourless powder soluble in water,It is white to slightly yellow crystalline odourless powder soluble in water, methanol, ethanol, chloroform and insoluble in ether having M.P=285methanol, ethanol, chloroform and insoluble in ether having M.P=285oo C.C. Toxic effectsToxic effects:: Nausea, vomiting and muscle plain, lower back pain, joint pain ,temporary hairNausea, vomiting and muscle plain, lower back pain, joint pain ,temporary hair loss, painful urination, blood in urine or stools, dizziness, double vision mayloss, painful urination, blood in urine or stools, dizziness, double vision may also occur, allergic reactions include rash, itching ,swelling and difficulty inalso occur, allergic reactions include rash, itching ,swelling and difficulty in breathing.breathing. Vincristine,Vinblastine,vinrosidine and vinleurosine are four closely relatedVincristine,Vinblastine,vinrosidine and vinleurosine are four closely related compounds have antitumour activity.compounds have antitumour activity. Semisynthetic derivative vinorelbine is also used as an antitumour agent.Semisynthetic derivative vinorelbine is also used as an antitumour agent.
  • 57. Structure of vinblastineStructure of vinblastine Chemically it is a complex structure consisting of two polycyclic units i.e. Catharathine and vindoline.
  • 58. SARSAR:: The presence of acetyl group is very essential for vinblastine to exhibit it Anti cancer activity. When this is hydrolysed activity gets destroyed. 2. When free hydroxyl grops were acetylated the drug lost its Antimalignant activity. 3.The potency of vinblastine reduces drastically when the double bonds Were initially hydrogenated and finally converted to carbinol group via reduction.
  • 59. Uses of vinblastine:Uses of vinblastine: 1.Vinblastine has been used in combination1.Vinblastine has been used in combination Therapies for the treatment of lymphomas,Therapies for the treatment of lymphomas, Testicular cancer and ovarian cancer.Testicular cancer and ovarian cancer. Hodgkin’s disease.Hodgkin’s disease. Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma Kaposi’s sarcomaKaposi’s sarcoma Mycosis fungoides.Mycosis fungoides. DoseDose: It is administered 0.3mg/kg for 3 weeks by: It is administered 0.3mg/kg for 3 weeks by I.V infusion.I.V infusion.
  • 60. Vincristine:Vincristine: Vincristine is also obtained from CatharanthusVincristine is also obtained from Catharanthus roseus, (vinca rosea)roseus, (vinca rosea) Chemically it consists of 2 polycyclic units.Chemically it consists of 2 polycyclic units. It is made up of 2 moieties namely catharanthineIt is made up of 2 moieties namely catharanthine and vindoline.and vindoline. It binds to the tubulin and has greater affinityIt binds to the tubulin and has greater affinity towards tubulin than the vinblastine.towards tubulin than the vinblastine. It is mainly used in combination therapy to treatIt is mainly used in combination therapy to treat Acute leukaemias, Hodgkin’s lymphoma, small cellAcute leukaemias, Hodgkin’s lymphoma, small cell Lung carcinoma and a variety of other tumoues.Lung carcinoma and a variety of other tumoues.
  • 61. Mechanisam of vincristine:Mechanisam of vincristine: Tubulin is a structural protein which is crucial toTubulin is a structural protein which is crucial to cell division.cell division. Genarally when the cell is about to divide, itsGenarally when the cell is about to divide, its Microtubules depolymerize to give tubulin.TheMicrotubules depolymerize to give tubulin.The tubulin is then repolymerized to formtubulin is then repolymerized to form Structure called a spindle which thenStructure called a spindle which then serves to push apart the two new cells andserves to push apart the two new cells and to act as a frame work on which theto act as a frame work on which the chromosome of the original cell arechromosome of the original cell are transferred to the nuclei of the daughtertransferred to the nuclei of the daughter cells.cells. Vincristine and vinblastine work by binding toVincristine and vinblastine work by binding to tubulin to prevent thistubulin to prevent this polymerization/depolymerization cycle takespolymerization/depolymerization cycle takes Place, and thus inhibit the growth of tumours.Place, and thus inhibit the growth of tumours.
  • 62. Physicochemical propertiesPhysicochemical properties:: It is white to yellow, crystalline,odourless,It is white to yellow, crystalline,odourless, Freely soluble in water insoluble in ether and having M.P=22Freely soluble in water insoluble in ether and having M.P=2200 C.C. Adverse effectsAdverse effects:: Loss of sleep, tendon reflexes, severe peripheral neuropathy, some time in severe casesLoss of sleep, tendon reflexes, severe peripheral neuropathy, some time in severe cases loss of motor function, foot drop, ataxia, bone marrow suppression( it is less commonloss of motor function, foot drop, ataxia, bone marrow suppression( it is less common than vinblastine), constipation, urinary disturbances and alopecia.than vinblastine), constipation, urinary disturbances and alopecia. Vincristine is used combination therapy toVincristine is used combination therapy to treat acute leukaemias, Hodgkin’s lymphoma, small cell lung cancer.treat acute leukaemias, Hodgkin’s lymphoma, small cell lung cancer. Burkitt’s lymphomaBurkitt’s lymphoma Wilm’s tumourWilm’s tumour Myeloma and neuroblastomaMyeloma and neuroblastoma Kaposi’s sarcomaKaposi’s sarcoma RhabdomyosarcomaRhabdomyosarcoma Brain, lung, breast and head and neck tumours.Brain, lung, breast and head and neck tumours. Therapeutic uses:
  • 63.  TheThe sulfur mustardssulfur mustards, of which, of which mustard gasmustard gas (1,5-(1,5- dichloro-3-thiapentane) is a member, are a class ofdichloro-3-thiapentane) is a member, are a class of relatedrelated cytotoxiccytotoxic,, vesicantvesicant chemical warfare agentschemical warfare agents withwith the ability to form largethe ability to form large blistersblisters on exposed skin. Pureon exposed skin. Pure sulfur mustards are colorless, viscous liquids at roomsulfur mustards are colorless, viscous liquids at room temperature. However, when used in impure form astemperature. However, when used in impure form as warfare agents they are usually yellow-brown in colorwarfare agents they are usually yellow-brown in color and have an odor resemblingand have an odor resembling mustard plantsmustard plants,, garlicgarlic oror horseradishhorseradish, hence the name Mustard agents can be, hence the name Mustard agents can be deployed on the battlefield via spraying from aircraft, ordeployed on the battlefield via spraying from aircraft, or more typically by means of air-dropped bombs ormore typically by means of air-dropped bombs or artillery shellsartillery shells. It has proved effective against entrenched. It has proved effective against entrenched troops and encampments. Without proper protection,troops and encampments. Without proper protection, mustard gas can be proved to be lethal to infantrymustard gas can be proved to be lethal to infantry
  • 64. Sulfur mustards and nitrogen mustardsSulfur mustards and nitrogen mustards AA blister agentblister agent (also known as a(also known as a vesicantvesicant ) is a chemical compound that) is a chemical compound that causes severe skin, eye and mucosal pain and irritation. They are named forcauses severe skin, eye and mucosal pain and irritation. They are named for their ability to cause severetheir ability to cause severe chemical burnschemical burns, resulting in large, painful water, resulting in large, painful water blistersblisters on the bodies of those affected. Although these compounds have beenon the bodies of those affected. Although these compounds have been employed on occasion for medical purposes, their most common use is asemployed on occasion for medical purposes, their most common use is as chemical warfare agentschemical warfare agents.. Most blister agents fall into one of three groups:Most blister agents fall into one of three groups: Sulfur mustardsSulfur mustards – A family of– A family of sulfursulfur-based agents, including the so-called-based agents, including the so-called "mustard gas"."mustard gas". Nitrogen mustardsNitrogen mustards – A family of agents similar to the sulfur mustards, but– A family of agents similar to the sulfur mustards, but based onbased on nitrogennitrogen instead of sulfurinstead of sulfur Mechanism of toxicityMechanism of toxicity The compound readily eliminates aThe compound readily eliminates a chloridechloride ion by intramolecularion by intramolecular nucleophilic substitutionnucleophilic substitution to form a cyclicto form a cyclic sulfoniumsulfonium ion. This veryion. This very reactive intermediate tends to bond to thereactive intermediate tends to bond to the guanineguanine nucleotidenucleotide inin DNADNA strands, which isstrands, which is particularly detrimental to cellular health.Thisparticularly detrimental to cellular health.This alkylation can lead toalkylation can lead to cellular deathcellular death andand cancercancer .Mustard gas is not very soluble in.Mustard gas is not very soluble in water but is very soluble in fat, contributing towater but is very soluble in fat, contributing to its rapid absorption into the skinits rapid absorption into the skin
  • 66. Physiological effectsPhysiological effects  Mustard gas has extremely powerfulMustard gas has extremely powerful vesicantvesicant effects on its victims. Additionally, it is stronglyeffects on its victims. Additionally, it is strongly mutagenicmutagenic andand carcinogeniccarcinogenic, due to its alkylating properties. It is also, due to its alkylating properties. It is also lipophiliclipophilic. Because people. Because people exposed to mustard gas rarely suffer immediate symptoms, and mustard-contaminated areasexposed to mustard gas rarely suffer immediate symptoms, and mustard-contaminated areas may appear completely normal, victims can unknowingly receive high dosages. However, withinmay appear completely normal, victims can unknowingly receive high dosages. However, within 24 hours of exposure to mustard agent,24 hours of exposure to mustard agent, victims experience intense itching and skinvictims experience intense itching and skin irritationirritation which gradually turns into large blisters filled with yellow fluid wherever the mustardwhich gradually turns into large blisters filled with yellow fluid wherever the mustard agent contacted the skin. These areagent contacted the skin. These are chemical burnschemical burns and they are very debilitating. If the victim'sand they are very debilitating. If the victim's eyes were exposed then they become sore, starting witheyes were exposed then they become sore, starting with conjunctivitisconjunctivitis,, after which the eyelidsafter which the eyelids swell, resulting in temporaryswell, resulting in temporary blindnessblindness. According to the Medical Management of Chemical. According to the Medical Management of Chemical Casualties handbook, there have been experimental cases in humans where the patient hasCasualties handbook, there have been experimental cases in humans where the patient has sufferedsuffered miosismiosis, or pinpointing of pupils, as a result of the, or pinpointing of pupils, as a result of the cholinomimeticcholinomimetic activity of mustard.[activity of mustard.[ citation neededcitation needed] At very high concentrations, if inhaled, mustard agent causes bleeding and] At very high concentrations, if inhaled, mustard agent causes bleeding and blistering within theblistering within the respiratory systemrespiratory system, damaging, damaging mucous membranesmucous membranes and causingand causing pulmonary edemapulmonary edema. Depending on the level of contamination, mustard gas burns can vary. Depending on the level of contamination, mustard gas burns can vary betweenbetween firstfirst andand second degree burnssecond degree burns , though they can also be every bit as severe,, though they can also be every bit as severe, disfiguring and dangerous asdisfiguring and dangerous as third degree burnsthird degree burns[3][3]. Severe mustard gas burns (i.e. where more. Severe mustard gas burns (i.e. where more than 50% of the victim's skin has been burned) are often fatal, with death occurring after somethan 50% of the victim's skin has been burned) are often fatal, with death occurring after some days or even weeks have passed. Mild or moderate exposure to mustard agent is unlikely to kill,days or even weeks have passed. Mild or moderate exposure to mustard agent is unlikely to kill, though victims invariably require lengthy periods of medical treatment andthough victims invariably require lengthy periods of medical treatment and convalescenceconvalescence beforebefore recovery is complete. Therecovery is complete. The mutagenicmutagenic andand carcinogeniccarcinogenic effects of mustard agent mean thateffects of mustard agent mean that victims who recover from mustard gas burns have an increased risk of developingvictims who recover from mustard gas burns have an increased risk of developing cancercancer in laterin later life.life.  Skin damage can be reduced ifSkin damage can be reduced if povidone-iodinepovidone-iodine in a base ofin a base of [1][1] is rapidly applied, but sinceis rapidly applied, but since mustard agent initially has no symptoms, exposure is usually not recognised until skin irritationmustard agent initially has no symptoms, exposure is usually not recognised until skin irritation begins—at which point it is too late for countermeasures. The vesicant property of mustard gasbegins—at which point it is too late for countermeasures. The vesicant property of mustard gas can be neutralised bycan be neutralised by oxidationoxidation oror chlorinationchlorination; household bleach (; household bleach (sodium hypochloritesodium hypochlorite) or) or decontamination solution "DS2" (2%decontamination solution "DS2" (2% NaOHNaOH, 70%, 70% diethylenetriaminediethylenetriamine, 28%, 28% ethylene glycol monomethyl etherethylene glycol monomethyl ether) can be used. After initial decontamination of the victim's) can be used. After initial decontamination of the victim's wounds is complete, medical treatment is similar to that required by any conventional burn. Thewounds is complete, medical treatment is similar to that required by any conventional burn. The
  • 67. Soldier with muster gas burns to hisSoldier with muster gas burns to his backback
  • 68. Mustard gasMustard gas  The most widely reported and, perhaps, the mostThe most widely reported and, perhaps, the most effective gas of the First World War waseffective gas of the First World War was mustard gasmustard gas, a, a vesicantvesicant, which was introduced by, which was introduced by Germany in July 1917 prior to theGermany in July 1917 prior to the Third Battle of YpresThird Battle of Ypres..[4][4] The Germans marked theirThe Germans marked their shells yellow for mustard gas and green for chlorineshells yellow for mustard gas and green for chlorine and phosgene, so they called the new gasand phosgene, so they called the new gas YellowYellow CrossCross Mustard gas is not a particularly effectiveMustard gas is not a particularly effective killing agent (though in high enough doses it iskilling agent (though in high enough doses it is fatal) but can be used to harass and disable thefatal) but can be used to harass and disable the enemy and pollute the battlefield. Delivered inenemy and pollute the battlefield. Delivered in artillery shells, mustard gas was heavier than air,artillery shells, mustard gas was heavier than air, and it settled to the ground as an oily liquidand it settled to the ground as an oily liquid resemblingresembling sherrysherry. Once in the soil, mustard gas. Once in the soil, mustard gas remained active for several days, weeks, or evenremained active for several days, weeks, or even months, depending on the weather conditions.months, depending on the weather conditions.[32][32]  The skin of victims of mustard gasThe skin of victims of mustard gas blistered, their eyes became very sore andblistered, their eyes became very sore and they began to vomit. Mustard gas causedthey began to vomit. Mustard gas caused internal and external bleeding and attackedinternal and external bleeding and attacked the bronchial tubesthe bronchial tubes , stripping off the mucous, stripping off the mucous membrane. This was extremely painful and mostmembrane. This was extremely painful and most soldiers had to be strapped to their beds. It usuallysoldiers had to be strapped to their beds. It usually took a person four or five weeks to die of mustardtook a person four or five weeks to die of mustard gas exposureMustard gas was the agent of choice,gas exposureMustard gas was the agent of choice, with the British stockpiling 40,719 tons, thewith the British stockpiling 40,719 tons, the Russians 77,400 tons, the Americans over 87,000Russians 77,400 tons, the Americans over 87,000 tons and the Germans 27,597 tons.tons and the Germans 27,597 tons.[38][38]
  • 70. Gases usedGases used  A=Allies, C=Central PowersA=Allies, C=Central Powers NameFirst useTypeUsed byNameFirst useTypeUsed by Xylyl bromideXylyl bromide[55][55]1914Lachrymatory, toxicBoth1914Lachrymatory, toxicBothChlorineChlorine[56][56] 1915Corrosive. Lung IrritantBoth1915Corrosive. Lung IrritantBothPhosgenePhosgene[56][56]1915Irritant - Skin and1915Irritant - Skin and mucous membranes. Corrosive, toxicBothmucous membranes. Corrosive, toxicBothBenzyl bromideBenzyl bromide[55][55] 1915LachrymatoryC1915LachrymatoryCChloromethyl chloroformateChloromethyl chloroformate[55][55]1915Irritant - Eyes, skin,1915Irritant - Eyes, skin, lungsBothlungsBothTrichloromethyl chloroformateTrichloromethyl chloroformate[55][55]1916Severe irritant, causes1916Severe irritant, causes burnsBothburnsBothChloropicrinChloropicrin[56][56]1916Irritant, lachrymatory, toxicBoth1916Irritant, lachrymatory, toxicBoth Stannic chlorideStannic chloride[55][55]1916Severe irritant, causes burnsAEthyl iodoacetate1916Severe irritant, causes burnsAEthyl iodoacetate[55][55] 1916Lachrymatory, toxicABromoacetone[55]1916Lachrymatory,1916Lachrymatory, toxicABromoacetone[55]1916Lachrymatory, irritantBothMonobromomethyl ethyl ketone[55]1916Lachrymatory,irritantBothMonobromomethyl ethyl ketone[55]1916Lachrymatory, irritantCAcrolein[55]1916Lachrymatory, toxicAHydrogen cyanide[55]irritantCAcrolein[55]1916Lachrymatory, toxicAHydrogen cyanide[55] (Prussic acid)1916Toxic, Chemical AsphyxiantAHydrogen sulfide[55](Prussic acid)1916Toxic, Chemical AsphyxiantAHydrogen sulfide[55] (Sulphuretted hydrogen)1916Irritant, toxicADiphenylchloroarsine[56](Sulphuretted hydrogen)1916Irritant, toxicADiphenylchloroarsine[56] (Diphenyl chlorasine)1917Irritant/SternutatoryCa-Chlorotoluene (Benzyl(Diphenyl chlorasine)1917Irritant/SternutatoryCa-Chlorotoluene (Benzyl chloride)1917Irritant, lachrymatoryCMustard gas[56] (Bis(2-chloroethyl)chloride)1917Irritant, lachrymatoryCMustard gas[56] (Bis(2-chloroethyl) sulfide)1917Vesicant (blistering agent), lung irritantBothBis(chloromethyl)sulfide)1917Vesicant (blistering agent), lung irritantBothBis(chloromethyl) ether (Dichloromethyl ether)1918Irritant, can blurether (Dichloromethyl ether)1918Irritant, can blur visionCEthyldichloroarsine[56]1918VesicantCvisionCEthyldichloroarsine[56]1918VesicantCNN-Ethylcarbazole1918Irritant-Ethylcarbazole1918Irritant
  • 71. Poison gas attack using gasPoison gas attack using gas cylenders in world war -1cylenders in world war -1
  • 72. ALTERNATIVES FORALTERNATIVES FOR ANTINEOPLASTICSANTINEOPLASTICS Cancer chemotherapy is now entering a new era which canCancer chemotherapy is now entering a new era which can be described as molecular targeted therapeutics-highlybe described as molecular targeted therapeutics-highly selective agents which target specific molecular targetsselective agents which target specific molecular targets that are abnormal or over expressed in the cancer cell.that are abnormal or over expressed in the cancer cell. Progress in this era has arisen from a better understandingProgress in this era has arisen from a better understanding of the cellular chemistry involved in particular cancerof the cellular chemistry involved in particular cancer cellscells The development of kinase inhibitors such asThe development of kinase inhibitors such as IMATINIB(glivec) is a much heralded illustration of thisIMATINIB(glivec) is a much heralded illustration of this approachapproach The use of antibodies and gene therapy is another area ofThe use of antibodies and gene therapy is another area of research which shows huge potential.research which shows huge potential.
  • 73. Finally, one of the best ways ofFinally, one of the best ways of reducing cancer is …..reducing cancer is …..  Firstly…Public education campaigns are important in highlighting the dangers ofFirstly…Public education campaigns are important in highlighting the dangers of smoking, because possibly as many assmoking, because possibly as many as 30%30% of cancers are caused by smoking,of cancers are caused by smoking, excessive drinking, and hazardous solvents, as well as promoting healthy diets andexcessive drinking, and hazardous solvents, as well as promoting healthy diets and lifestyles.lifestyles.  Secondly, anotherSecondly, another 30%30% of cancers are diet related that’s why everybody should takeof cancers are diet related that’s why everybody should take healthy diets and lifestyles.healthy diets and lifestyles.  The benefits of eating high-fibre foods, fruit, and vegetables are clear.The benefits of eating high-fibre foods, fruit, and vegetables are clear.  Infact, there have been various research projects aimed at identifying the specificInfact, there have been various research projects aimed at identifying the specific chemicals in these foods which are responsible for this protective property. Forchemicals in these foods which are responsible for this protective property. For example,example,  DithiolDithiolthiones are a group of chemicals inthiones are a group of chemicals in brobroccoccolili, cauliflower, and cabbage, cauliflower, and cabbage which appear to have protective properties, one of which involves the activation ofwhich appear to have protective properties, one of which involves the activation of enzymes in the liver to detoxify carcinogens.enzymes in the liver to detoxify carcinogens.  GenisteinGenistein is a protective compound found inis a protective compound found in soy productssoy products used commonly inused commonly in Asian populations have a low incidence of breast, prostate, colon cancers.Asian populations have a low incidence of breast, prostate, colon cancers.  Epigallocatechin gallate, an antioxidant present inEpigallocatechin gallate, an antioxidant present in green teagreen tea, is another potential, is another potential protective agent.protective agent.  Synthetic drugs are also being investigated as possible cancer preventivesSynthetic drugs are also being investigated as possible cancer preventives ((finasfinasteride, aspirin, ibuprofen, andteride, aspirin, ibuprofen, and difluoromethyldifluoromethylornithine).ornithine).

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