ANTICANCER DRUGS

1. Anti-cancer Therapy
Dr. S. Nawazish-i-Husain
Pharmacology
Pharm D 3rd Profession
2014-2015

2. What is Cancer?
 Cancer is the deregulation of normal
cellular processes. Cells that have been
transformed tend to proliferate in an
uncontrolled and deregulated way and, in
some cases, to metastasize (spread).
 Cancer is not one disease, but a group of
more than 100 different and distinctive
diseases.
 Cancer can involve any tissue of the body
and take on many different forms in each
area.
 Cancer is the 2nd leading cause of death in
the U.S., surpassed only by heart disease.

3. What Happens in Cancer Cells?
 Cancer cells become deregulated in many different ways
One way:
Mutations in one or more mitotic checkpoints
allow the cell to move from one phase of mitosis to
another unchecked.
Another way:
Mutations in cellular machinery itself so that
mitotic errors are not properly detected/repaired,
and the cell is allowed to move through mitosis
unchecked.

4. Characteristics of Cancer Cells
 Cancer involves the development and
reproduction of abnormal cells
 Cancer cells are usually
nonfunctional
 Cancer cell growth is not subject to
normal body control mechanisms
 Cancer cells eventually metastasize
to other organs via the circulatory and
lymphatic systems

5. Proliferation of cells
 Proliferating cells
 Based on the DNA changes in cells, proliferating cycle
of tumor cells can be divided into 4 phases
 Pre-synthetic phase (Gap 1 phase or G1 phase).
Cells chiefly make preparations for the synthesis of
DNA.
 Synthetic phase (S phase). Cells are synthesizing
their DNA.
 Post-synthetic phase (Gap 2 phase or G2 phase).
DNA
duplication has been finished and they are equally
divided to
the two of future sub-cells.
 Mitosis phase (M Phase). each cell is divided into two

6. Non-proliferating cells
Non-proliferating cells
• Non-proliferating cells include G0 phase cells
(resting-phase cells)
• G0 phase cells have proliferation ability but do not
divide temporarily
• When proliferating cells are suffered heavy casualties,
G0 phase cells will get into proliferating cycle and
become the reasons of tumor recurrence
• G0 phase cells are usually not sensitive to
antineoplastic drugs, which is an important obstacle
to treat tumor with chemotherapy

7. Stages of Mitosis
 Interphase: Technically not
part of mitosis, but rather
encompasses stages G1,
S, and G2 of the cell cycle
which prepare the cell for
mitosis.
 Prophase: Chromatin in
nucleus condense;
nucleolus disappears.
Centrioles begin moving to
opposite ends of the cell
and fibers extend from the
centromeres.
 Metaphase: Spindle fibers
align the chromosomes
along the middle of the cell
nucleus. This line is
referred to as the
‘metaphase plate.’
 Anaphase: The paired
chromosomes separate at
the kinetochores and move
to opposite sides of the
cell. Motion results from the
physical interaction of polar
microtubules.

8. Stages of Mitosis
 Telophase: Chromatids
arrive at opposite poles of
cell, and new membranes
form around the daughter
nuclei. The chromosomes
disperse.
 Cytokinesis: Results when
a fiber ring composed of a
protein called actin around
the center of the cell
contracts, pinching the cell
into two daughter cells,
each with one nucleus.

9. Mitosis Summary
 Mitosis is the process by which a cell duplicates the
chromosomes in its cell nucleus in order to
generate two, identical, daughter nuclei.
 It is followed immediately by cytokinesis, which
divides the nuclei, cytoplasm, organelles and cell
membrane into two daughter cells containing
roughly equal shares of these cellular components.
 Mitosis and cytokinesis together define the mitotic
(M) phase of the cell cycle.
 Mitosis is a normal cellular process necessary to
sustain life, but its deregulation in one form or
another is found in all cancer cells.
 Mitosis can often become abnormal by the change
in, or absence of, the normal mitotic checkpoints.

10. Mitotic Checkpoints
 Mitotic checkpoints are points in the cell cycle
which act to ensure correct transmission of
genetic information during cell division. These
checkpoints look for abnormalities within the
cycle, specifically chromosomal aberrancy
(deviation from normal course).
 Checkpoints take place towards the end of each
phase of mitosis and must be passed before the
cell can get clearance to enter into the next stage
of mitosis.
 If errors are found during checkpoints, the cell acts
quickly to correct them, arresting cell growth and
not proceeding with mitosis until the error has been
fixed.
 If these errors cannot be fixed, the cell normally
undergoes apoptosis, or programmed cell death.

11. How ‘Cancer’ Arises
 The cell is allowed to move through the cell cycle
and grow unchecked, and more mutations are
accumulated over time that extend past the cell
cycle to the cellular machinery itself.
 These mutations, in combination with the genetic
mutations accrued through abnormal mitotic
progression, eventually cause the cell to be
completely deregulated in its growth and
proliferation.
 It becomes unstoppable and even immortal.

12. Types of Cancer
Categorized based on the functions/locations of the cells from
which they originate:
1. Carcinoma - skin or in tissues that line or cover internal
organs. E.g., Epithelial cells. 80-90% reported cancer cases
are carcinomas.
2. Sarcoma - bone, cartilage, fat, muscle, blood vessels, or
other connective or supportive tissue.
3. Leukemia - White blood cells and their precursor cells such
as the bone marrow cells, causes large numbers of abnormal
blood cells to be produced and enter the blood.
4. Lymphoma - cells of the immune system that affects
lymphatic system.
5. Myeloma - B-cells that produce antibodies- spreads through
lymphatic system.
6. Central nervous system cancers - cancers that begin in the
tissues of the brain and spinal cord.

13. Treatment of Cancer
• Surgery to remove solid tumors
• Radiation to kill cancer cells that have spread
to adjacent local or regional tissues
• Chemotherapy to kill cancer cells located
throughout the body
• Antineoplastic drugs cannot differentiate
between normal and cancerous cells

14. 14
New types of cancer treatment
Hormonal Treatments: These drugs are designed to prevent cancer cell growth by
preventing the cells from receiving signals necessary for their continued growth
and division. E.g., Breast cancer – tamoxifen after surgery and radiation
Specific Inhibitors: Drugs targeting specific proteins and processes that are
limited primarily to cancer cells or that are much more prevalent in cancer cells.
Antibodies: The antibodies used in the treatment of cancer have been
manufactured for use as drugs. E.g., Herceptin, avastin
Biological Response Modifiers: The use of naturally occuring, normal proteins to
stimulate the body's own defenses against cancer. E.g., Abciximab, rituxmab
Vaccines: Stimulate the body's defenses against cancer. Vaccines usually contain
proteins found on or produced by cancer cells. By administering these proteins,
the treatment aims to increase the response of the body against the cancer
cells.

15. Nucleic Acids – A Review
• Class of macromolecule
– Monomer = nucleotide
• Phosphate
• Sugar
• Nitrogenous base
– Determine order of amino acids
– Source of genetic information which is passed
between generations

16. Nucleic Acids – A Review
Types
DNA
• Double stranded
• Deoxyribose
• Bases:
• Cytosine, guanine,
adenine, thymine
RNA
• Single stranded
• Ribose
• Bases:
• Cytosine, guanine,
adenine, uracil

17. Nucleotide Arrangement
Nucleotides are the
building blocks of DNA
Phosphate
Sugar
Base

19. Cell Division in Eukaryotes
• Multicellular organisms grow larger and
replace damaged or dead cells through the
process of cell division.
• Why must cells split and divide? Why can’t
cells just grow larger?
– Surface area-to-volume ratio
• How does the cell cycle compare in various
organisms?
– Prokaryotic vs. eukaryotic

20. 8.2 The Phases of the Cell Cycle
• The cell cycle is the complete series of events from
one cell division to the next.
• When a cell no longer has enough surface area
(contact with the outside) to support its volume
(what needs to be accomplished inside) the cell must
divide and become two cells.
– Two resulting cells are called daughter cells
• Phases of the Cell cycle:
– G1 (Gap 1)
– S phase (synthesis)
– G2 (Gap 2)
– Mitosis (actual cell division)

22. The Stages of Cell Division
• Cytokinesis
– Divides the cell in two
– In animals: plasma membrane pinches in forming
a cleavage furrow until the cell completely
pinches apart into two separate cells
• Begins during anaphase
– In plants: cell plate forms down center of cell and
ultimately forms two separate cells
• Begins during telophase

23. Checkpoints
• Things can go wrong during the cell cycle. If
these problems go unchecked or uncorrected
serious problems could result in the organism
• Specific proteins detect mistakes and the cell
cycle is halted until the mistake is fixed
– Ex: p53
• Inactivates formation of G1 cyclin-kinase system
• Gene responsible for halting the cell cycle until all
chromosomes have replicated properly
• Defects in this gene is a precursor to cancer

25. Cancer Genes
• Proto-oncogenes promote cell division while
• tumor suppressors inhibit cell division
– In cancer cells both pathways are disrupted.
1. Mutated proto-oncogene= oncogene (cancer gene)
2. Oncogene causes cells to leave G0 and proceed through
cell division
3. Mutated tumor suppressor genes causes removal of
checkpoint system
4. Cells continue to divide repeatedly
5. Cancer cells metastasize (spread throughout the body)

26. Progression of
Cancer
NORMAL
CELLS
BENIGN
fast dividing
cells, not
really toxic,
only cause
mechanical
damage
MALIGNANT
toxic, cause
local toxicity
and
inflammation
METASTATIC
travel from
one place to
another.
The real
killer

28. 28
Cancer Chemotherapy (Background)
A. Most of the recent progress using antineoplastic therapy is based on:
1. Development of new combination therapy of using existing drugs.
2. Better understanding of the mechanisms of antitumor activity.
3. Development of chemotherpeutic approaches to destroying
micrometastases
4. Understanding the molecular mechanisms concerning the initiation of
tumor growth and metastasis.
5. Recognition of the heterogeneity of tumors
B. Recently developed principles which have helped guide the treatment of
neoplastic disease
1. A single clonogenic cell can produce enough progeny to kill the host.
2. Unless few malignant cells are present, host immune mechanisms do not
play a significant role in therapy of neoplastic disease.
3. A given therapy results in destruction of a constant percentage as
opposed to a constant number of cells, therefore, cell kill follows first order
kinetics.

29. E. The Main Goal of Antineoplastic Agents
IS to eliminate the cancer cells without affecting normal tissues (the concept of
differential sensitivity). In reality, all cytotoxic drugs affect normal tissues as
well as malignancies - aim for a favorable therapeutic index (aka therapeutic
ratio).
Therapeutic Index =
LD50
-----
ED50
A therapeutic index is the lethal dose of a drug for 50% of the population (LD50)
divided by the minimum effective dose for 50% of the population (ED50).
29

30. Infrequent scheduling of
treatment courses.
Prolongs survival but does not cure.
More intensive and
frequent treatment.
Kill rate > growth rate.
Untreated patients
F. The effects of tumor burden, scheduling, dosing, and initiation/duration of
treatment on patient survival.
Early surgical removal of the
primary tumor decreases the tumor
burden. Chemotherapy will remove
persistant secondary tumors.
30

31. 31
General rules of chemotherapy
Aggressive high-dose chemotherapy
•Dose- limiting is toxicity towards normal cells
•Cyclic regimens - repeated administrations with appropriate intervals
for regeneration of normal cells (e.g., bone marrow cells)
•Supportive therapy - to reduce toxicity
hematotoxicity – bone marrow transplantation, hematopoietic
growth factors
Specific antagonists: antifolate (methotrexate) – folate
(leucovorin)
MESNA - donor of –SH groups, decreased urotoxicity of
cyclophosphamide. Detoxifying agent.
dexrazoxane: chelates iron, reduced anthracycline cardiotoxicity
amifostine: reduces hematotoxicity, ototoxicity and neurotoxicity
of alkylating agents

32. 32
General rules of chemotherapy
•Combination of several drugs with different mechanisms of action,
different resistance mechanisms, different dose-limiting toxicities.
•Adjuvant therapy: Additional cancer treatment given after the primary
treatment to lower the risk that the cancer will come back. Adjuvant
therapy may include chemotherapy, radiation therapy, hormone therapy,
targeted therapy, or biological therapy.
•Neoadjuvant therapy: Treatment given as a first step to shrink a tumor
before the main treatment, which is usually surgery, is given. Examples of
neoadjuvant therapy include chemotherapy, radiation therapy, and
hormone therapy. It is a type of induction therapy.

33. 33
General rules of chemotherapy
•Supportive therapy:
-Antiemetics (5-HT3 -antagonists)
-Antibiotic prophylaxis and therapy (febrile neutropenia)
-Prophylaxis of urate nephropathy (allopurinol)
-Enteral and parenteral nutrition
-Pain – analgesic drugs
-Psychological support

34. Cell Cycle specificity

35. 35
DNA
RNA
Protein
tubulin
Purines and
Pyrimidines
Asparaginase
Tubulin binders
Alkylating agents
Topoisomerase Inh.
Antimetabolites
Antimetabolits
Chemotherapy: Mechanisms of Action
1

36. Mechanism of antineoplastic
drugs
Most antineoplastic drugs act on the proliferating cycle of cell
(1)destruction of DNA or inhibition of DNA duplication
– e.g. alkylating agents, mitomycin C
(2) inhibition of nucleic acid (DNA and RNA) synthesis
– e.g. 5-fluorouracil, 6-mercaptopurine, methotrexate, cytarabine, etc.
(3) Interfering with the transcription to inhibit RNA synthesis
– e.g. dactinomycin, dauoruicin, doxorubicin
(4) Inhibition of protein synthesis
– e.g. vinca alkaloids, epipodophylotoxins, paclitaxel
(5) Interfering with hormone balance
– e.g. adrenal corticosteroids, estrogens, tamoxifen etc.

37. Classification of
Antineoplastic Drugs
On the basis of antineoplastic action on the phase of proliferation cycle,
drugs are classified as
• Cell cycle non-specific agents (phase nonspecific
agents, CCNSA) (e.g. alkylating agents)
• Act in all proliferating phases, even the G0
• effects are stronger
• Cell cycle specific agents (phase specific agents,
CCSA). (e.g. antimetabolites, vinca alkaloids)
• just act on specific phases of the cell cycle
• effects are comparatively weaker

38. Classification of
Antineoplastic Drugs
On the basis of source and mechanisms of
cytotoxic action, the drugs are also classified
as:
• Alkylating agents
• Antimetabolites
• Natural products
• Hormones and antagonists
• Miscellaneous agents

39. Major Clinically Useful Alkylating Agents
39
Bis(mechloroethyl)amines Nitrosoureas Aziridines
Cancer Chemotherapy
Chapter 55. B.G. Katzung

40. (Ⅰ) Alkylating Agents
Alkylating agents act via a reactive alkyl (-RCH2-CH2
+-)
group that reacts to form covalent bonds with nucleic
acids
• Cross-linking of the two strands of DNA,
preventing replication or DNA breakage
• Phase-nonspecific cytotoxic agents
• kill rapidly proliferating cells, as well as
non-proliferating cells

41. (Ⅰ) Alkylating Agents
Mechlorethamine
• the first drug used in the treatment of
cancer
• Mainly used for Hodgkin's disease and non-
Hodgkin's lymphomas
Cyclophosphamide
• Most widely used in clinical therapy for
treatment of cancer
• It has no antineoplastic action outside the
body and must be activated in the liver

42. 42
H2N
O
N
N
HN
N
HO
O
O
P
O
NH2
O
N
N
NH
N
O
O
P
OH
O
N
R
Crosslinking: Joining two or more molecules by a covalent bond. This can either
occur in the same strand (intrastrand crosslink) or in the opposite strands of the
DNA (interstrand crosslink). Crosslinks also occur between DNA and protein.
DNA replication is blocked by crosslinks, which causes replication arrest and
cell death if the crosslink is not repaired.
An Example of DNA Crosslinking

43. 43
Cancer Chemotherapy
Chapter 55. B.G. Katzung
Alkylating Agents (Covalent DNA binding drugs)
1. The first class of chemotherapy
agents used.
2. They stop tumour growth by
cross-linking guanine
nucleobases in DNA double-helix
strands - directly attacking DNA.
3. This makes the strands unable to
uncoil and separate.
4. As this is necessary in DNA
replication, the cells can no longer
divide.
5. Cell-cycle nonspecific effect
6. Alkylating agents are also
mutagenic and carcinogenic
A
T
C G
C
G
G
A
T
G C

44. E.g., Mechlorethamine (Nitrogen Mustards)
44

45. 45
Cyclophosphamide
Cyclophosphamide is an alkylating agent. It is a
widely used as a DNA crosslinking and cytotoxic
chemotherapeutic agent.
•It is given orally as well as intravenously with efficacy.
•It is inactive in parent form, and must be activated to
cytotoxic form by liver CYT450 liver microsomal
system to 4-Hydroxycyclophamide and
Aldophosphamide.
•4-Hydroxycyclophamide and Aldophosphamide are
delivered to the dividing normal and tumor cells.
•Aldophosphamide is converted into acrolein and
phosphoramide mustard.
•They crosslink DNAs resulting in inhibition of DNA
synthesis

46. 46
Cyclophosphamide Metabolism
Inactive

47. 47
Cyclophosphamide
Clinical Applications:
1. Breast Cancer
2. Ovarian Cancer
3. Non-Hodgkin’s Lymphoma
4. Chronic Lymphocytic Leukemia (CLL)
5. Soft tissue sarcoma
6. Neuroblastoma
7. Wilms’ tumor
8. Rhabdomyosarcoma
Cancer Chemotherapy
Chapter 55. B.G. Katzung

48. 48
Cyclophosphamide
Clinical Applications:
1. Breast Cancer
2. Ovarian Cancer
3. Non-Hodgkin’s Lymphoma
4. Chronic Lymphocytic Leukemia (CLL)
5. Soft tissue sarcoma
6. Neuroblastoma
7. Wilms’ tumor
8. Rhabdomyosarcoma
Cancer Chemotherapy
Chapter 55. B.G. Katzung

49. 49
Cyclophosphamide
Major Side effects
1. Nausea and vomiting
2. Decrease in PBL count
3. Depression of blood cell counts
4. Bleeding
5. Alopecia (hair loss)
6. Skin pigmentation
7. Pulmonary fibrosis
Cancer Chemotherapy
Chapter 55. B.G. Katzung

50. 50
Ifosphamide
Mechanisms of Action
Similar to cyclophosphamide
Application
1. Germ cell cancer,
2. Cervical carcinoma,
3. Lung cancer
4. Hodgkins and non-Hodgkins lymphoma
5. Sarcomas
Major Side Effects
Similar to cyclophosphamide

51. 51
1. Mechanism of
Action
2. Clinical application 3. Route 4. Side effects
a. Nitrogen
Mustards
A. Mechlorethamine DNA cross-links,
resulting in
inhibition of DNA
synthesis and
function
Hodgkin’s and non-
Hodgkin’s lymphoma
Must be given
Orally
Nausea and vomiting,
decrease in
PBL count, BM
depression, bleeding,
alopecia, skin
pigmentation, pulmonary
fibrosis
B. Cyclophosphamide Same as above Breast, ovarian, CLL, soft
tissue sarcoma, WT,
neuroblastoma
Orally and I.V. Same as above
C. Chlorambucil Same as above Chronic lymphocytic
leukemia
Orally effective Same as above
D. Melphalan Same as above Multiple myeloma, breast,
ovarian
Orally effective Same as above
E. Ifosfamide Same as above Germ cell cancer, cervical
carcinoma, lung, Hodgkins
and non-Hodgkins
lymphoma, sarcomas
Orally effective Same as above
A. Alkylating agents
Cancer Chemotherapy
Chapter 55. B.G. Katzung

52. 52
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
b. Alkyl Sulfonates
A. Busulfan Atypical alkylating agent. Chronic granulocytic
leukemia
Orally effective Bone marrow depression,
pulmonary fibrosis, and
hyperuricemia
c. Nitrosoureas 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
A. Carmustine DNA damage, it can
cross blood-brain barrier
Hodgkins and non-
Hodgkins lymphoma, brain
tumors, G.I. carcinoma
Given I.V. must be
given slowly.
Bone marrow depression,
CNS depression, renal
toxicity
B. Lomustine Lomustine alkylates and
crosslinks DNA, thereby
inhibiting DNA and RNA
synthesis. Also
carbamoylates DNA and
proteins, resulting in
inhibition of DNA and RNA
synthesis and disruption of
RNA processing.
Lomustine is lipophilic and
crosses the blood-brain
barrier
Hodgkins and non-
Hodgkins lymphoma,
malignant melanoma and
epidermoid carcinoma of
lung
Orally effective Nausea and vomiting,
Nephrotoxicity, nerve
dysfunction
C. Streptozotocin DNA damage pancreatic cancer Given I.V. Nausea and vomiting,
nephrotoxicity, liver toxicity
A. Alkylating agents

53. 53
d. Ethylenimines 1. Mechanism of
Action
2. Clinical application 3. Route 4. Side effects
A. Triethylene
thiophosphoramide
(Thio-TEPA)
DNA damage,
Cytochrome
P450
Bladder cancer Given I.V. Nausea and vomiting,
fatigue
B.
Hexamethylmelamine
(HMM)
DNA damage Advanced ovarian tumor Given orally after
food
Nausea and vomiting, low
blood counts, diarrhea
d. Triazenes 1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
A. Dacarbazine (DTIC) Blocks, DNA, RNA and
protein synthesis
Malignant Melanoma,
Hodgkins and non-Hodgkins
lymphoma
Given I.V. Bone marrow depression,
hepatotoxicity, neurotoxicity,
bleeding, bruising, blood clots,
sore mouths.
A. Alkylating agents
Cancer Chemotherapy
Chapter 55. B.G. Katzung

54. 54
Summary
Cancer Chemotherapy
Chapter 55. B.G. Katzung

55. (Ⅱ) Antimetabolites
• Antimetabolites are analogues of normal
metabolites and act by competition,
replacing the natural metabolite and then
subverting cellular processes
• Examples of antimetabolites include:
• Folic acid antagonists (e.g. Methotrexate)
• Antipyrimidines (e.g. 5-Fluorouracil,
Cytarabine)
• Antipurines (e.g. 6-Mercaptopurine)

58. (Ⅱ) Antimetabolites
Methotrexate
• Mimics folic acid, which is needed for
synthesis of DNA, RNA and some
amino acids
• It acts mainly on the S phase cells
• Severe myelosuppression

59. (Ⅱ) Antimetabolites
6-Mercaptopurine
• A structural analogue of hypoxanthin
• It must be converted intracellularly to
the nucleotide 6-mercaptopurine
ribose phosphate and 6-methyl-
mercaptopurine ribonucleotide, and
then inhibit purine biosynthesis,
causing inhibition of biosynthesis of
nucleic acid

60. (Ⅱ) Antimetabolites
5-Fluorouracil (5-FU)
• Analogue of uracil
• Metabolically activated to a nucleotide
(FdUMP)
• It inhibits the synthetase of
deoxythymidine monophosphate,
inhibiting DNA synthesis. Also, its
metabolite interferes RNA synthesis
• A phase-specific drug

62. (Ⅲ) Natural Products
• Antibiotics
• Vinca alkaloids
• Biologic response modifiers
• Enzymes
• Epipodophyllotoxins
• Taxanes

63. (Ⅲ) Natural Products
Antibiotic antineoplastic agents
• Damage DNA in cycling and
noncycling cells
• Dactinomycin (actinomycin D)
This drug binds noncovalently to double-
stranded DNA and inhibits DNA-directed
RNA syntheisis
Dactinomycin is a phase-nonspecific
agent, but it is more active against G1
phase cells

64. 64
Tubulin Binding
Agents
a

Polymerization
tubulin
Depolymerization
e.g., Vincristine,
Vinblastine, Vindesine
Vinorelbine: Inhibition
of mitotic spindle
formation by binding to
tubulin.
M-phase of the cell
cycle.
e.g., Paclitexal: binds
to tubulin, promotes
microtubule formation
and retards
disassembly; results in
mitotic arrest.
Paclitexal (taxol)
Vincristine

65. B. Natural Products
65
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
A. Vincristine Cytotoxic: Inhibition of mitotic
spindle formation by binding
to tubulin.
M-phase of the cell cycle.
Metastatic testicular cancer,
Hodgkins and non-Hodgkins
lymphoma, Kaposi’s sarcoma,
breast carcinoma, chriocarcinoma,
neuroblastoma
I.V. Bone marrow depression, epithelial
ulceration, GI disturbances,
neurotoxicity
B. Vinblastine Methylates DNA and inhibits
DNA synthesis and function
Hodgkins and non-Hodgkins
lymphoma, brain tumors, breast
carcinoma, chriocarcinoma,
neuroblastoma
I.V. Nausea and vomiting, neurotoxicity,
thrombocytosis, hyperuricemia.
1. Antimitotic Drugs
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
Paclitaxel (Taxol) Cytotoxic: binds to
tubulin, promotes
microtubule formation
and retards disassembly;
mitotic arrest results
Melanoma and carcinoma of
ovary and breast
I.V. Myelodepression and
neuropathy
2. Antimitotic Drugs

66. 66
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
A. Etoposide Binds to and inhibits
Topoisomerase II and its
function. Fragmentation
of DNA leading to cell
death, apoptosis.
Testicular cancer, small-cell
lung carcinoma, Hodgkin
lymphoma, carcinoma of
breast, Kaposi’s sarcoma
associated with AIDS
I.V. Myelosuppression, alopecia
B. Teniposide Same as above Refractory acute
lymphocytic leukemia
I.V. Myelosuppression,
3. Epipodophyllotoxins (These are CCS)
Accumulation of
single- or double-
strand DNA breaks,
the inhibition of
DNA replication and
transcription, and
apoptotic cell
death.
Etoposide acts
primarily in the
G2 and S
phases of the
cell cycle
Act on Topoisomerase II

67. 67
Cancer Chemotherapy
Chapter 55. B.G. Katzung
4. Antibiotics (CCS)
1. Mechanism of Action 2. Clinical application 3.
Route
4. Side effects
a. Dactinomycin
(ACTINOMYCIN
D)
It binds to DNA and
inhibits RNA synthesis,
impaired mRNA
production, and protein
synthesis
Rhabdomyosarcoma and
Wilm's tumor in children;
choriocarcinoma (used with
methotrexate
I.V. Bone marrow depression,
nausea and vomiting, alopecia,
GI disturbances, and
ulcerations of oral mucosa
b. Daunorubicin
(CERUBIDIN)
Doxorubicin
(ADRIAMYCIN)
inhibit DNA and RNA
synthesis
Acute lymphocytic/granulocytic
leukemias; treatment of
choice in nonlymphoblastic
leukemia in adults when
given with cytarabine
I.V. Side effects: bone marrow
depression, GI disturbances
and cardiac toxicity (can be
prevented by dexrazoxane)
inhibit DNA and RNA
synthesis
Acute leukemia, Hodgkin's
disease, non Hodgkin's
lymphomas (BACOP regimen),
CA of breast & ovary,
small cell CA of lung,
sarcomas, best available agent
for metastatic thyroid CA
I.V. Cardiac toxicity, Doxorubicin
mainly affects the heart
muscles, leading to tiredness or
breathing trouble when climbing
stairs or walking, swelling of the
feet .
c. Bleomycin
(BLENOXANE)
fragment DNA chains
and inhibit repair
Germ cell tumors of testes and
ovary, e.g., testicular
carcinoma (can be curative
when used with vinblastine &
cisplatin), squamous cell
carcinoma
Given
I.V. or
I.M.
Mucosocutaneous reactions
and pulmonary fibrosis; bone
marrow depression much less
than other antineoplastics
Inhibit DNA and RNA syntheses

68. 68
Cancer Chemotherapy
Chapter 55. B.G. Katzung
5. Enzymes: L-asparaginase
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
L-asparaginase Hydrolyzes L-asparagine (to
L-aspartic acid) an essential
amino acid to many leukemic
cells
Acute lymphocytic leukemia,
induction of remission in acute
lymphoblastic leukemia when
combined with vincristine,
prednisone, and anthracyclines
I.V. or
I.M.
Nausea and vomiting, Poor appetite,
Stomach cramping, Mouth sores,
Pancreatitis. Less common: blood
clotting

69. 69
C. Antimetabolites
Reduced
Folate
Carrier
protein
MTX
Kills cells
during
S-phase
(Folic acid analog)
MTX
polyglutamates
Are selectively
retained
In tumor cells.
Folic acid is a growth factor that provides single
carbons to the precursors used to form the
nucleotides used in the synthesis of DNA and
RNA. To function as a cofactor folate must be
reduced by DHFR to THF.
*
*
* * *
Cancer Chemotherapy
Chapter 55. B.G. Katzung

70. 70
Cancer Chemotherapy
Chapter 55. B.G. Katzung
1. Mechanism of Action 2. Clinical application 3. Route 4. Side effects
1.
Methot
rexate
inhibits formation of
FH4
(tetrahydrofolate)
from folic
acid by inhibiting
the enzyme
dihydrofolate
reductase (DHFR);
since FH4 transfers
methyl groups
essential to DNA
synthesis and
hence DNA
synthesis blocked.
Choriocarcinoma,
acute lymphoblastic
leukemia (children),
osteogenic
sarcoma, Burkitt's
and other non-
Hodgkin‘s
lymphomas, cancer
of breast, ovary,
bladder, head &
neck
Orally
effecti
ve as
well
as
given
I.V.
bone marrow
depression,
intestinal lesions
and interference
with embryogenesis.
Drug interaction:
aspirin and
sulfonamides
displace
methotrexate
from plasma
proteins.
C. Antimetabolites

71. 71
1. Mechanism of
Action
2. Clinical application 3. Route 4. Side effects
2 Pyrimidine Analogs:
Cytosine Arabinoside
inhibits DNA
synthesis
most effective agent for induction of
remission in acute myelocytic
leukemia; also used for induction of
remission acute lymphoblastic leukemia,
non-Hodgkin's lymphomas; usually used
in combination chemotherapy
Orally
effective
bone marrow
depression
1. Mechanism of
Action
2. Clinical application 3. Route 4. Side effects
2 Purine analogs:
6-Mercaptopurine (6-
MP) and Thioguanine
Blocks DNA
synthesis by
inhibiting conversion
of
IMP to AMPS and to
XMP as well as
blocking conversion
of AMP to
ADP; also blocks first
step in purine
synthesis.
Feedback inhibition
blocks DNA
synthesis by
inhibiting conversion
of IMP to
XMP as well as GMP
to GDP; also blocks
first step in purine
synthesis by
feedback inhibition
most effective agent for induction of
remission in acute myelocytic
leukemia; also used for induction of
remission acute lymphoblastic leukemia,
non-Hodgkin's lymphomas; usually used
in combination chemotherapy
Orally
effective
bone marrow
depression,

72. 72
Cancer Chemotherapy
Chapter 55. B.G. Katzung
6. Drug Resistance
One of the fundamental issue in cancer chemotherapy is the development
of cellular drug resistance. It means, tumor cells no longer respond to
chemotherapeutic agents. For example, melanoma, renal cell cancer,
brain cancer often become resistant to chemotherapeutic agents.
A few known reasons:
1. Mutation in p53 tumor suppressor gene occurs in 50% of all tumors.
This leads to resistance to radiation therapy and wide range of
chemotherapy.
2. Defects or loss in mismatch repair (MMR) enzyme family. E.g., colon
cancer no longer respond to fluoropyrimidines, the thiopurines, and
cisplatins.
3. Increased expression of multidrug resistance MDR1 gene which
encodes P-glycoprotein resulting in enhanced drug efflux and reduced
intracellular accumulation. Drugs such as athracyclines, vinca
alkaloids, taxanes, campothecins, even antibody such as imatinib.

73. 73
Summary
1. The main goal of anti-neoplastic drug is to eliminate the cancer cells
without affecting normal tissues.
2. Log-Kill Hypothesis states that a given therapy kills a percentage of
cells, rather then a constant number, therefore, it follows first order
kinetics. Aim for a favorable therapeutic index.
3. Early diagnosis is the key.
4. Combination therapy and adjuvant chemotherapy are effective for small
tumor burden.
5. Two major classes of antineoplastic agents are:
a. Cell Cycle Specific and
b. Cell Cycle Non-Specific agents
5. Because chemotherapeutic agents target not only tumor cells, but also
affect normal dividing cells including bone marrow, hematopoietic, and
GI epithelium. Know what the side effects are.
6. Drug resistance is often associated with loss of p53 function, DNA
mismatch repair system, and increased MDR1 gene expression.

74. Antimitotic Agents
 Three distinct classes of antimitotic agents
have been identified thus far.
1.) Taxanes; include: paclitaxel and
docetaxel.
2.) Vinca alkaloids; include: vincristine,
vinblastine, vindesine, and vinorelbine.
3.) Colchicine.
 Administrated via intravenous infusion.

75. Taxanes (First Antimitotic Group)
 Prevent the growth of cancer cells by
affecting microtubules.
 Overall, they encourage microtubule
formation, then they stop the microtubules
from being broken down so that the cells
become so clogged with microtubules that
they cannot continue to grow and
divide. This results in the cell’s arrest in
mitosis.
 Eventually, cell DEATH by apoptosis.

76. Taxanes: Paclitaxel
 Paclitaxel [Taxol] was the
first compound of the
series to be discovered and
used in cancer treatment.
 Used in the treatment of:
ovarian cancer, breast
cancer, AIDS-related
Kaposi's sarcoma and lung
cancer.
 Side effects include: bone
marrow loss,
hypersensitivity, muscle
aches, peripheral
neuropathy, bradycardia
and tachycardia.

77. Taxanes: Docetaxel
 Docetaxel [Taxotere] is
partially-synthetic
derivative of Taxol and
results from the
modification of paclitaxel’s
side chain.
 While it is paclitaxel’s
structural analog, it is much
more potent in terms of
potential patient toxicity.
 It acts to kill cancer cells in
the same way as paclitaxel.

78. Taxanes: Docetaxel (cont.)
 Useful in the treatment of: mainly prostate
cancer, but also breast, ovarian and lung
cancer.
 Must be co-administered with
dexamethasone to prevent progressive,
often disabling, fluid retention in the
peripheries, lungs and abdomen.
 Side effects are more severe but more
short-lived than Taxol and include:
leukopenia, peripheral edema, neutropenia.

79. Taxanes: Complicating
Factors
 Resistance to taxanes is a complicating factor to
successful treatment and is often associated with
increased expression of the mdr-1 gene and its
product, the P-glycoprotein.
 Other resistant cells have B-tubulin mutations
which inhibit the binding of taxanes to the correct
place on the microtubules; this renders the drug
ineffective. In addition, some resistant cells also
display increased aurora kinase, an enzyme that
promotes completion of mitosis. Some cells
display a heightened amount of survivin, an anti-
apoptotic factor.
 Side effects can be debilitating.
 These drugs are very expensive and must be
administered in large amounts at once due to the
fact that much of the drug is excreted in the urine
or allocated to the plasma. This large

80. (Ⅲ) Natural Products
Vinca alkaloids
• Vincristine and vinblastine are alkaloids
isolated from this periwinkle plant
• bind to tubulin, interfere with the
assembly of spindle proteins during mitosis
• Act at M phase to inhibit mitosis, blocking
proliferating cells as they enter metaphase
• Both can cause bone marrow suppression
and neurotoxicity

81. Vinca Alkaloids: Vinblastine
 Vinblastine [Velban]
was the first of the
Vincas to be used in
the treatment of
cancer.
 Useful in the treatment
of: bladder and
testicular cancers,
Kaposi’s sarcoma,
neuroblastoma and
Hodgkin’s disease.
 Side effects include:
leukopenia, GI
disturbances, cellulitis,
phlebitis.

82. Vinca Alkaloids: Vincristine
 Vincristine [Oncovin]
 Useful in the treatment of:
pediatric leukemias and
lymphomas, non-Hodgkin’s
lymphoma, neuroblastoma
and rhabdomyosarcoma.
 Better tolerated by children
than adults.
 Side effects:
myelosuppression,
hyponatremia,
numbness/tingling of
extremities, loss of deep
tendon reflexes, and loss of
motor function.
 Intrathecal administration
results in fatal central
neurotoxicity.

83. Vinca Alkaloids: Vinorelbine
 Vinorelbine
[Navelbine]
 Used in the treatment
of: lung carcinoma,
breast cancer.
 Side effects include:
granulocytopenia,
thrombocytopenia,
myelosuppression,
and less neurotoxicity
than all of the other
Vincas.

84. Vinca Alkaloids:
Vindesine
 Vindesine [Eldisine]
 Useful in the
treatment of: breast
and lung cancer,
leukemia.
 Side effects:
immunodeficiency,
anemia, myalgia,
fatigue, mouth
ulcers, GI upset.

85. Vinca Alkaloids: Complicating
Factors
 Resistance to the Vinca alkaloids comes in the
form of cross-resistance due to the structural
similarity of the four compounds, and their
antitumor effects are blocked by multidrug
resistance in which tumor cells become cross-
resistant to a wide variety of agents after exposure
to a single drug. Resistant cells can also display
chromosomal abnormalities consistent with gene
amplification, and these cells contain increased
levels of the P-glycoprotein. Other forms of
resistance stem from mutations in B-tubulin that
prevent the binding of the inhibitors to their target.
 Also, because of the heavy concentration of
microtubules in the brain and the drug’s disruption
of this, patients treated with Vinca alkaloids can
experience severe neurotoxicity.

86. Drug Resistance is a REAL
Problem for Cancer Patients
 Multidrug resistance is a major drawback of cancer
chemotherapy and can result in patients becoming
immune to the effects of many different drugs at
once.
 A major mechanism of multidrug resistance occurs
via an over-expression of ATP transmembrane
efflux pumps which pump the drug outside of the
cell after its entrance.
 Resistance can often result in patient death as a
result of lack of effective treatment available.
 This remains a problem with all anti-cancer
therapies.

87. (Ⅳ) Hormones and
antagonists
• Adrenocortical steroids to inhibit the
growth of cancers of lymphoid tissue
and blood
• Oestrogen antagonists (tamoxifen) is
indicated for breast cancer
• Oestrogen is used for prostatic
cancers

88. L-Asparaginase
 derived from bacteria
 L-Asparaginase hydrolyzes blood asparagine and, thus, deprives the
tumor cells of this amino acid, which is needed for protein synthesis
 administered either IV or intramuscularly, because it is destroyed by
gastric enzymes.
 Toxicities include a range of hypersensitivity reactions , a decrease
in clotting factors, liver abnormalities, pancreatitis, seizures, and
coma due to ammonia toxicity

90. (Ⅴ) Miscellaneous agents
Hydroxyurea
• Hydroxyurea inhibits ribonucleotide
reductase, inhibiting DNA synthesis
• It is specific for the cells in S phase
• Bone marrow suppression

91. Toxicity of Antineoplastic
Drugs
Short-term toxicity
• Common side reactions usually
appear
earlier and many of them occur in rapid
proliferating tissues such as marrow,
gastrointestinal tract, and hair follicle.
• myelosuppression
• gastrointestinal tract symptom
• alopecia

92. Toxicity of Antineoplastic
Drugs
Long-term toxicity
The long-term toxicity mainly occurs in
the patients who received chemotherapy
over a long time period
• carcinogenesis
• teratogenesis
• sterility