IVRI, Izatnagar,Bareilly

1. Presented by-
Pankaj Kumar Patel ( M-5718)
Sumit Kumar (M-5781)
Presented to-
Dr. MADHU C.L.
NEOPLASM AND ANTINEOPLASTIC DRUGS

2. CANCER
• Cancer known as a malignant neoplasm,
-is a broad group of diseases involving –
1.Unregulated Cell growth, Cell devision
2.Grow uncontrollably,
 3.Invading nearby parts of the body or
 4.Spread to more distant parts of the body
through the lymphatic system or bloodstream.
3+4= METASTASIS
Not all tumors are cancerous; benign tumors do not invade neighboring
tissues and do not spread throughout the body.

4. • .

5. RISK FACTORS
1. Tobacco ( Humans)
2. Sunlight
3. Ionizing radiation
4. Certain chemicals and other substances
5. Some viruses and bacteria
6. Certain hormones
7. Family history of cancer
8. Alcohol (Humans)
9. Poor diet, lack of physical activity,
or being overweight

6. Normal Cell
DNA Damage
Mutations in the genome of
somatic cells
Alteration of genes that
regulates apoptosis
Expression of altered gene products
Loss of regulatory gene product
MALIGNANT NEOPLASM
Activation of growth
promoting oncogene
Inactivation of cancer
suppressor genes
Acquired
(environmental DNA
damaging agents)
Chemicals
Radiation
viruses
Successful DNA repair
Failure of DNA repair
CARCINOGENESIS
•Clonal expansion
•Additional mutations
•Heterogeneity
.

8. CANCER TYPES
• Based on the functions/locations of the cells from which they originate:
 Carcinoma: a tumor derived from epithelial cells,
cells lines the surface of skin and organs
 Sarcoma: a tumor derived from muscle, bone, cartilage, fat or connective
tissues.
 Leukemia: a cancer derived from white blood cells or their precursors.
 Lymphoma: a cancer of bone marrow derived cells
that affects the lymphatic system.
 Myelomas: a cancer involving the B lymphocytes
responsible for the production of antibodies

9. Cell Cycle and Clinical Importance
• All cells—normal or neoplastic—must
traverse before and during cell division
• Malignant cells spend time in each phase -
longest time at G1, but may vary
• Many of the effective anticancer drugs exert
their action on cells traversing the cell cycle -
cell cycle-specific (CCS) drugs
• Cell cycle-nonspecific (CCNS) drugs -
sterilize tumor cells whether they are cycling
or resting in the G0 compartment
• CCNS drugs can kill both G0 and cycling
cells
• CCS are more effective on cycling cells

10. Cell Cycle and Clinical condition
• Information is valuable in knowing - mode of action, indications, and
scheduling of cell cycle-specific (CCS) and cell cycle-nonspecific
(CCNS) drugs
• CCS – effective against hematologic malignancies
and in solid tumors with large growth fraction
• CCNS drugs – solid tumors with low growth fraction
• CCS drugs are given after a course of CCNS

15. DIAGNOSIS OF CANCER
Biopsy - involves histological examination by a pathologist of a piece of tissue.
Imaging techniques –
• CT scan
• MRI
Laboratory test
Tumor markers(produced by cancer)
Example:
 CA15-3 - Breast cancer.
 CA19-9 - Gastrointestinal tumours.
 CA-125 - Ovarian cancers.
 PSA - Prostate cancers.

17. Treatment of Cancer
1-CANCER CURE
When all cancer cell have been eradicated
2- PALLIATION 
To reduce pain include cell sense of well being of correct some
physiological malfunction
3- REMISSION 
When all clinical sign and symptoms of cancer have disappeared but
microscopic foci of cancer cells may remain

18. Different regimens in cancer therapy
• Depend on 
1. Growth rate of tumor
2.Tumor size
3.Location of tumor
4. Also look drug dose and time of administration

19. Some Rational for combinational chemotherapy
• Additive effects of tumor are
more pronounced than on
normal tissue
• A decreased tendency towards
the development of resistance
• Combination may be less Toxic
• Iatrogenic stem cells respond
in are better way

20. Certain rules and guides in combination of
chemotherapeutic agents
• Each drug should be active on tumors
• Drug should have different most
• Toxicity should overlapped minimally
• Each drug should be administered at it’s optimal
dosage and schedule

21. Drugs Based on Cell Cycle
• CCNS: Nitrogen Mustards, Cyclphosphamide, chlorambucil, carmustine,
dacarbazine, busulfan, L-asparginase, cisplatin, procarbazine and actinomycine D
• CCS:

22. ANTI CANCER DRUG CLASSIFICATION

23. MECHANISAM OF ANTICANCER DRUGS
• Alkylating agents  Act by forming covalent bonds with
DNA and thus impeding replication
• Antimetabolites Block the metabolic pathways involved in
DNA synthesis
• Cytotoxic antibiotics Substances of microbial origin that
prevent mammalian cell division
• Plant derivatives (vinca alkaloids, taxanes, campothecins) 
affect microtubule function and hence the
formation of the mitotic spindle.
• Hormones  the most important are steroids,
namely glucocorticoids, oestrogens and
androgens, as well as drugs that suppress
hormone secretion / antagonise hormone action

24. ANTI CANCER DRUG CLASSIFICATION (CYTOTOXICITY)

28. ALKALYSING AGENT

29. Subgroups of Alkylating Agents
1) Nitrogen mustards
2) Nitrosoureas
3) Alkyl sulfonates
4) Platinum Coordination Compounds
1-Nitrogen Mustards
Eg.: Mechlorethamine, cyclophosphamid, melphalan & chlorambucil
Mechlorethamine
- First alkylating agent employed clinically
- Can crosslink DNA
- Lymphoreticular neoplasm , mast cell tumour
- Dog and cate @ 5 mg/m2 i/v as a single dose or 2-4 devided dose on succesive days

30. .
Cyclophsphamid
-It acts as cytotoxic and immunosuppressor agent.
-Prodrug which must be activated by the cytochrome p450 system, which turns it
into a nitrogen mustard.
-most widely used alkylating agent
Dog and Cat @ 50mg/m2/day
Orally or i/v for 4days
Toxicity/ Side Effects
- bone marrow depression
- severe nausea and vomiting
- acute hemorrhagic cystitis
- sterility
- hypersensitivity reactions

31. 2-Nitrosoureas
Broad spectrum of Antineoplastic agent
- Inhibits synthesis of both DNA and RNA, as well as proteins
- These drugs are highly lipophilic, so they can easily cross blood-brain-
barrier, and are great for CNS tumors.
-
Major toxicity- they are highly mutagenic and highly carcinogenic.
DELAYED bone marrow depression & Pulmonary fibrosis.
Clinical uses
- primary and metastasis tumors of the brain
- Adenocarcinoma of stomach, colon, and rectal cancer
- Hepatocarcinoma
Eg. Streptozotocine – islet cell carcinoma @ 35mg/kg weekly by slow i/v

32. 3-Alkyl Sulfonates
Busulfan
Clinical use
Great effect on for Chronic granulocytic Leukemia
Toxicity/ Side Effects
- Pulmonary infiltrates
- pulmonary fibrosis( BUSLFAN LUNG)
- Tonic-clonic seizures in epileptics

33. 4-Platinum Coordination Compounds
Cisplatin
• Forms crosslinks within DNA strands.
• Cis-platin is not really an “alkylating” agent,
• same mechanism as the alkylating agents,
it is placed within that group.
Clinical Uses
- Very powerful against TESTICULAR CANCER
- Also good for carcinomas of ovary, bladder, head, and neck
Toxicity/ Side Effects
- Renal tubular damage (minimized via massive hydration coupled with anti-emetics)
- Ototoxicity and peripheral neuropathy
- VERY SEVER vomiting
Carboplatin:
is a derivative of cisplatin with less nephero- ,neuro- & ototoxicity.

34. Antimetabolites (CCS)
• A chemical that Block the metabolic pathways involved in
DNA synthesis
Classified into:
1- Folic acid analogues
2- Purine analogues
3- Pyrimidine analogues
Uses
• leukemia.
• Inflammatory bowel disease and ulcerative colitis
• It is widely used as immunosuppressant in transplantations to control rejection
reactions.

35. .
1-Folic acid analogues
Methotrexate
dog @5mg/m2 orally on day1 and 5 of each week
2-Purine analogues
Mercaptopurine (6−mercaptopurine, or 6−MP) -
dog @50mg/m2 /day orally
Azathioprine
3-Pyrimidine analogues
5-flurouracil (5-FU) –
@100mg/m2 once weekly
Cutaneous carcinoma topical 2% cream
Cytarabine -
canine and feline lymphosarcoma @100-150mg/m2 for 4 days slow IV or IM

36. MECHANISM OF ACTION OF METHOTREXATE
Inhibits
Dihydrofolate reductase
(DHFR).
decreased production of
compounds adenine, guanine
and thymidine and the amino
acids methionine and serine,
depletion of thymidine.
depressed DNA, RNA, and
protein synthesis and,
ultimately, to cell death

37. MECHANISM OF ACTION OF 6-MERCAPTOPURINE
6-Mercaptopurine
Penetrates target cells
Converted to the nucleotide analog
monoribonucleotidase
Inhibit the first step of de novo
purine -ring biosynthesis
Non-functional RNA and DNA.

38. MECHANISM OF ACTION OF 5-FLUOROURACIL
5-Fluorouracil
competes with deoxyuridine
monophosphate for
thymidylate synthase
reduce the thymidine
lack of thymidine,
leading to imbalanced cell
growth
DNA synthesis decreases

39. CYTARABINE

40. MECHANISM OF ACTION OF GEMCITABINE
 Gemcitabine
 incorporated into cytosine
containing sites in the growing
strand
 inhibits DNA synthesis
 Gemcitabine diphosphate
Inhibits ribonucleotide
reductase
se generation of
deoxynucleoside
triphosphates
se DNA synthesis

41. Antitumor antibiotics (CCNS)
1- D actinomycin
• Isolated Streptomyces.
• First antibiotic shown to have anti-cancer activity
It inhibits transcription by binding to DNA and form Stable transcription
initiation complex
preventing elongation by RNA polymerase.
stabilize the action of Topoisomerase II
 DOG & CAT @ 1.5mg/m2, IV once weekly
2-Doxorubicin (adriamycin)
• Doxorubicin is anthracyclin antibiotic
• Inserting itself between adjacent base pair causing local uncoiling thus blocking DNA
and RNA synthesis.
• Inhibition of topoisomerase II enzyme (responsipole for DNA repair).
• DOG & CAT @ 20-30 mg/m2 IV, every 3 week upto 6-7 dosase

42. MECHANISM OF ACTION OF DOXORUBICIN AND DAUNORUBICIN
Doxorubicin and daunorubicin
bind
sugar-phosphate backbone of DNA.
local uncoiling.
Blocks DNA & RNA synthesis
Catalyzed breakage supercoiled DNA
strands
irreparable breaks.
Catalyzes the formation of free radicals.
 reduce molecular O2,
 producing superoxide ions and
hydrogen peroxide,
single-strand scission of DNA

44. .
Uses
• Multiple cancers including breast, bone, ovarian & leukemia.
• Acute lymphocytic leukemia (ALL).
Side effects
• Irreversible heart problems specially heart failure
• Hypersensitivity, myelosuppression
• Nausea, vomiting & diarrhea
• Urine and tears may take on a red color.
3-Mitomycin−C
• Mitomycin−C is an antitumor antibiotic.
• Mechanistically however, it belongs to DNA alkylating agents.
• Upon bioactivation inside the cell ,it preferentially alkylates O6 of guanine base in DNA
leading to cross linking of DNA.
• It also degrade DNA through formation of free radicals.
Side effects
-Bone marrow suppression.
-Lung fibrosis may occur

45. .
4-Bleomycin
• CHELATING GLYCOPEPTIDES ANTIBIOTICS
• It is cytotoxic in any phase of the cycle even on G0 phase . Chelate copper or
iron, interact with oxygen and produce superoxide radicals
• Bleomycin degrade performed DNA causing chain fragmentation and release of
free bases through the formation of free radicals (superoxide and hydroxyl
radicals).
• Squamous cell Carcinoma @ 10mg/m2, IV,IM / SC daily 3-4 days
Uses
 cancer of the head and neck, skin, esophagus, lung, testis, and genitourinary
tract.
Side effects
• Pulmonary fibrosis
• Raynaud's phenomenon (which affects the fingers and toes, may involve pain, pale
color, and abnormal sensation as burning)
• In addition, headache, and nausea and vomiting may occur.

46. MECHANISM OF ACTION OF BLEOMYCIN
DNA-bleomycin-Fe2+ complex
oxidation
bleomycin-Fe3+.
React with oxygen to forms
superoxide or hydroxyl radicals
liberated electrons ,
Attack the phosphodiester bonds of
DNA,
strand breakage and chromosomal
aberrations

47. Plant alkaloids (Phase specific)
1-The vinca alkaloids
Vincristine & vinblastine (M-phase)
Mechanism of action
. Vincristine binds to tubulin
Inhibiting polymerization of microtubule structures
 Disruption of the microtubules arrests mitosis in metaphase.
 The vinca alkaloids therefore affect all rapidly dividing cell types including cancer cells, but
also intestinal epithelium and bone marrow.
VINCRISTINE@ 0.5mg/m2 ,IV, weekly
VINBLASTINE@2mh/m2,IV, weekly
Side effects
Peripheral neuropathy.
Accidental injection of vinca alkaloids into the spinal canal (intrathecal administration) is highly
dangerous, with a mortality rate approaching 100%. (vinblastin is less neurotoxic)
Uses
• Malignant lymphomas and leukemia.

48. MECHANISM OF ACTION OF VINCA ALKALOIDS

49. .
2-Taxanes
Paclitaxel & docetaxel
BARK OF WESTERN YELLOW TREE
it is used for treatment of lung, ovarian and breast cancer.
Mechanism of action
Paclitaxel binds to the β subunit of tubulin ,the resulting microtubule/paclitaxel
complex.
Prevent depolymerization of microtubulrs
( causing imbalance of tubules and microtubule dynamic equilibrium)
Side effects
Bone marrow suppression and neurotoxicity

50. .
3-Etoposide
• Chemically it is deriven from Podophyllotoxin,
plant glycoside of mandrake root
• Inhibitor enzyme topoisomerase II. In G2 phase
cause breaks in the DNA inside the cancer cells and
 prevent them from further dividing and multiplying.
Then the cells die.
Side effect
• Vomiting & alopecia
• Bone marrow suppression
uses
• treatment of testicular cancer
• small cell lung cancer.

51. MECHANISM OF ACTION OF ETOPOSIDE &TENIPOSIDE
Etoposide and its analog, teniposide are
Semisynthetic derivatives of
the plant alkaloid,
Block cells in the late S to
G2 phase of the cell cycle.
target  topoisomerase II.
Binding of the drugs to the
enzyme-DNA complex
cleavable form of the
complex
 irreversible double-strand
breaks

52. Miscellaneous cytotoxic drugs
1-Crisantaspase
• Preparation of asparaginase kills cancer cells by breaking
down certain protein (L−asparagine) that is necessary for
survival and growth of certain tumors incapable of forming such
protein e.g. acute lymphoblastic leukemia ALL.
• Fortunately, normal cells are not dependent on L−asparagine for
survival.
• Asparaginase is mainly given in combination with vincristine and
steroids (either prednisone or dexamethasone).
• DOG & CAT @10000-30,000 iu/m2, IV or IP once weekly

53. MECHANISM OF ACTION OF L-ASPARAGINASE

54. Hormones and hormone antagonists
1-Corticosteroids
Corticosteroids have broad use in cancer treatment
Immunosuppressive mechanism
• Glucocorticoids suppress the CMI.
• They act by inhibiting genes that code for the cytokines interlukin and TNF-γ,
• the most important of which is the IL-2. The inhibition of cytokine production reduces
the T cell proliferation.
• Glucocorticoids also suppress the expansion and antibody synthesis.
Side effects
• Hyperglycemia
• reduced bone density
• increased visceral and truncal fat deposition
• adrenal insufficiency
• muscle breakdown (proteolysis)
The most common corticosteroids used in cancer treatment are:
PREDNISONE @10-40mg/m2 orally OD/ BID daily, gradually dicrease
to 10-20 mg/m2 on alternate days

55. .
2-Estrogens
Mainly used in androgen dependent prostatic tumors
3-Gonadotropin−releasing hormone analogues
Goserelin Acetate·
Synthetic hormone that acts similarly to the naturally occurring
gonadotropin−releasing hormone (GnRH).
In male, this results in decreased blood levels of the male hormone testosterone.
In female, it decreases blood levels of the female hormone estrogen.
Estrogen increases the risk of ENDOMETRIAL CARCINOMA
CAT @ 0.5mg/kg orally daily for 2 week,
Side effects
• Sweating , impotence ,sterility & gyncomestia
• Depression

56. Hormone antagonists
Tamoxifen
• Selectively inhibits the effects of estrogen on breast tissue,
• selectively mimicking the effects of estrogen on bone (by increasing bone
mineral density) and uterine tissues.
• tamoxifen an excellent therapeutic agent against breast cancer.
• it is known to compete with estrogen by binding to estrogen receptors on the
membrane of target cells, thus limiting the effects of estrogen on breast tissue.
• Tamoxifen may also has other anti−tumor activities :affecting oncogene
expression& promotion of apoptosis (cancer cell death)
• Dose- @ 40mg/m2 every 12 hrs orally for 1 week
Adverse Effects
• CNS: Depression
• GI: Nausea, vomiting
• Hematological: Hypercalcemia
• Dermatologic: Hot flashes, skin rash

58. TOXIC EFFECTS OF ANTI CANCER DRUGS
• Bone marrow toxicity (myelosuppression) with decreased leucocyte
production and thus decreased resistance to infection
• Impaired wound healing
• Loss of hair (alopecia)
• Damage to gastrointestinal epithelium
• Depression of growth in children
• Sterility
• Teratogenicity.
• .

59. .
 Acute toxicity
 Vomiting
 Allergic reactions
 Arrhythmias
 Delayed effects
 Mucositis
 Alopecia
 Bone marrow suppression
 Chronic toxicities
 Heart
 Kidney
 Liver
 Lungs

60. Countering the Toxicities
• A Intermittent therapy
• Folinic acid rescue
• Systemic Mesna (sodium-2-mercaptoethane sulfonate) administration
and irrigation by acetylcysteine – detoxify toxic metabolites
• Ondansetron
• Hyperurecaemia : uricosuric agents like allopurinol
• Platelet and granulocyte transfusion
• Granulocyte colony stimulating factors (GM-CSF/G-CSF) – recovery
of garnulocytopenia

61. Resistance
• Intrinsic:
Some tumor types, e.g. malignant melanoma, renal cell cancer, and brain
cancer, exhibit primary resistance, i.e. absence of response on the first
exposure, to currently available standard agents
• Acquired:
– Single drug: change in the genetic apparatus of a given tumor cell with
amplification or increased expression of one or more specific genes
– Multidrug resistance:
• Resistance to a variety of drugs following exposure to a single variety of drug
• increased expression of a normal gene (the MDR1 gene) for a cell surface
glycoprotein (P-glycoprotein) involved in drug efflux