This document provides an overview of chemotherapy for cancer. It begins by defining cancer and describing the hallmarks of cancer cells, such as immortality and lack of contact inhibition. It then discusses various types of chemotherapy drugs, including alkylating agents, antimetabolites, taxanes, and hormones. It also addresses general toxicity of chemotherapy drugs and resistance. Radiation therapy is mentioned as another treatment strategy. The document covers many aspects of chemotherapy for cancer in a comprehensive manner.

1. CHEMOTHERAPY OF
CANCER
-BY
KAVYA VAJRESH
MPHARMACY
(Pharmacology)

2.  Introduction
 Properties Of Cancer
 Cancer Cell Transformation
 Biochemical Pathway
 Types
 Drugs Acting Directly On Cells
 General Toxicity Of Cytotoxic Drugs
 Hormones
 Radiation Therapy
 Future Strategies

3. CANCER
Group of diseases involving abnormal cell growth with the potential to invade
or spread to other parts of the body.
Growth regulators
Killing pathways
• Mutations (physical/chemical carcinogens)
• Eating habits
• Virus
• Inheritance

4. Hallmarks of cancer:
Immortality
Rapid growth and division
(Faulty check points; Lots of growth receptors)
No contact inhibition
Proliferation(metastases)
Low nutrient and oxygen requirement( promoting angiogenesis)

5. Cancer cells can go against the immune system
• Natural killer cells
• Cytokines
Cancer cells hide its antigenic sites ,therefore NK cells are not able to
recognize

6. CANCER CELL TRANSFORMATION
• Irradiation
• Virus
• Lifestyle
Avian Leukosis Virus insertion leads
to production of MYC without
regulatory site
UV Irradiation:
Causes dimerization of pyrimidine's
leading to faulty DNA

7. Oncogene : Gain of function
Tumor suppressor gene : Loss of function
CANCER
Changes in gene, due to mutations
It can be:
Point mutations:
Ex: Rendering P53 inactive ;hyper activation of
Ras
Chromosomal mutations:
• Deletion
• Translocation
• Insertion

8. BIOCHEMICAL PATHWAY
NORMAL CELL CANCER CELL

9. Cancers are classified according to the
• kind of fluid or tissue from which they originate, or
• according to the location in the body where they first
developed
 Carcinoma : (>80%)
Found in epithelial tissue, which covers surfaces of organs,
glands, or body structures.
EX: cancer of the lining of the stomach ;Many carcinomas affect
organs involved with secretion, such as breasts that produce milk.
 Sarcoma : (<2%)
A sarcoma is a malignant tumor growing from connective
tissues, such as cartilage(chondrosarcoma), fat, muscle,
tendons, and bones osteosarcoma
TYPES

10.  Lymphoma :
Lymphoma refers to a cancer that originates in the nodes or glands
of the lymphatic system(WBC)
Lymphomas are classified into two categories:
• Hodgkin lymphoma( presence of Reed-Sternberg cell, which is
abnormal lymphocytes that may contain more than one nucleus)
and
• Non-Hodgkin lymphoma.
 Leukemia:
also known as blood cancer,
is a cancer of the bone marrow

11. DRUGS ACTING DIRECTLY ON CELLS
 Alkylating Agents
• Nitrogen Mustards
• Ethylenimine
• Nitrosoureas
 Anti metabolites
• Folate antagonist
• Purine antagonist
• Pyrimidine antagonist
 Vinca alkaloids
 Taxanes
 Epipodohyllotoxin
 Camptothecin analogues
 Antibiotics

12. ALKYLATING AGENTS
• Produce highly reactive carbonium ion intermediates, which
transfer alkyl groups by forming covalent bonds
• Position 7 of guanine residue is susceptible
• Thus, cross linking or abnormal base pairing or scission of DNA
strand occurs
• cell cycle non-specific

13. NITROGEN MUSTARDS
DRUG ROUTE A.E OTHERS
Mechlorethamine Only
I.V
Nausea, vomiting,
sloughing(collapse
due to extravasation)
Cyclophosphamide
(prodrug)
Oral,
I.V,
I.M
Alopecia;
cystitis
*Active metabolites(Aldophosphamide;
Phoshoramide)-occurs in liver
*Immunosuppressant
*Chloramphenicol-Retards metabolism
Ifofosfamide Hemorrhagic cystitis
(Due to acrolein-corrosive
liver metabolite) (- by
mesna)
Use-carcinoma, sarcoma, lymphoma
Chlorambucil oral Slow acting; active on lymphoid tissue
Long term maintenance therapy
Melphalan Oral,
inj
Bone marrow
depression;
Diarrhea;
Use-Multiple myeloma, ovarian cancer

14. DRUG ROUTE A.E OTHERS
Thio-
TEPA(Ethylenimine)
inj Highly toxic(Not
used)
Busulfan (Alkyl
sulfonate)
oral Hyperuricaemia;
Pulmonary
fibrosis; infertility
Specific for myeloid
elements (granulocytes, RBC
precursors)
Nitrosoureas(Alkyl
sulfonate)
oral Visceral fibrosis;
renal damage
Cross BBB-used in Brain
tumors
Dacarbazine
(Triazine)
inj Has inhibitory action on
RNA, Proteins;
Use-Hodgkin's;
Activated-liver

15. ANTI METABOLITES
Folate antagonist: (Methotrexate)
• Inhibition(Primarily DNA) is irreversible (50,000times high
affinity)
• Cell cycle specific(S-phase)
Route: Oral(50%bound); I.M;I.V
• Salicylates, sulfonamides displace from binding sites
and Inc. toxicity by decreasing renal secretion
Use: Choriocarcinoma; Leukemia; Arthritis; Psoriasis;
Immunosuppressant
A.E: Low dose-megaloblastic anemia
High dose-Pancytopenia
Desquamation(Shedding of skin); bleeding
MOA: Competitively inhibit use of normal substrate or get incorporated
forming dysfunctional macromolecules.

16. Purine Antagonist:
DRUG USE A.E OTHERS
6-
Mercaptopur
ine;
Thioguanine
Leukemia;
Choriocarcin
oma
Metabolized
by: Xanthine
oxidase (6-
MP)
S-
methylation
(TG)
Azathioprine Immunosupp
ressant
(Suppress cell
mediated
immunity)
;Arthritis
Reversible
jaundice’
Hypeuricemi
a(-By
Allopurinol)
Route-oral
Metabolized
by: Xanthine
oxidase or
methylation
Fludarabine Lymphatic
leukemia;
Non-
Hodgkin's
lymphoma
Chills; Fever;
Myelosuppre
ssion
Active-
triphosphate
form ; It also
inhibits DNA
polymerase

17. Pyrimidine Antagonist:
5-fluoro2-deoxy-
uridine
monophosphateDeoxy
uridilic acid Deoxy thymidilic acid
5-Fluorouracil:
Itself gets incorporated into nucleic acids ,
leading to toxicity)
Route: Oral;I.V.;Topical
Use: Cutaneous carcinoma;
Breast;Colon;Urinary bladder
Cytarabine:
Phosphorylated(Triphosphate)
Inhibits DNA-polymerase ; Blocks generation of
cytidilic acid
Cell cycle specific(S phase)
Route: Inj
Use: Leukemia; Lymphoma

18. VINCA ALKALOIDS
 Vincristine(Oncovin):
Rapidly acting
Use: leukemia; sarcoma;
carcinoma; Hodgkin's
A.E: Neuropathy; Alopecia
 Vinblastine:
Use: Hodgkin's; Testicular
carcinoma
A.E: Bone marrow depression

19. TAXANES
 Paclitaxel:
Obtained from bark of western yew tree
Increase polymerization of tubulin, inhibits reorganization of microtubules
Use: Metastatic ovarian and breast carcinoma; head and neck cancer; prostate
cancer
A.E: Myelosuppression; stocking and glove neuropathy; arthralgia; myalgia;
edema
 Docetaxel:
More potent
Use: ovarian and breast cancer; Pancreatic; Gastric
A.E: Neutropenia; Arrhythmia; Fall in BP

20. EPIPODOHYLLOTOXIN
Etoposide:
 Semisynthetic derivative of
podophyllotoxin(glycoside)
 Arrests cells in G2 phase
 Resealing of strand is prevented.
Use: Testicular tumor; lung cancer; Lymphoma; Bladder
carcinoma
A.E: Alopecia; leucopenia
Route: inj

21. CAMPTOTHECIN ANALOGUES
• Obtained rom Chinese tree
• Allows single strand breaks but not resealing after untwisting.
• Act in S phase, arrests at G2 phase(Damage during replication)
Topotecan:
Use: Metastatic ovary carcinoma; Lung cancer
A.E: Neutropenia; anorexia; Diarrhea
Route: inj
Irinotecan:
• Prodrug; Decarboxylated I liver to active metabolite
• Inhibits AchE (Cholinergic effects are seen) ,
Can be suppressed by prior atropinization
Use: Metastatic colorectal carcinoma; Lung cancer
A.E: Neutropenia; Thrombocytopenia; Diarrhea;
Hemorrhage.
Route: inj

22. ANTIBIOTICS Practically all of them intercalate between DNA strands and interfere with template
function.
DRUG USE AE MOA OTHERS
Actinomycin D Wilm’s tumor;
Rhabdomyosarcoma (In
striated muscle);
Choriocarcinoma
Stomatitis(Sores in mouth);
Diarrhea; Erythema;
Desquamation of skin;
Alopecia; Bone marrow
depression
binds DNA at the
transcription
initiation complex
and prevents
elongation of RNA
chain
Route:
Inj
Daunorubicin;
Doxorubicin
Leukaemia Cardio toxicity;
Arrhythmia;
Hypotension; CHF;
Alopecia; Stomatitis
Breaks DNA by
Inhibiting
TopoisomeraseII
Generates quinone
type free radicals
Route:
Inj
Mitoxantrone Lymphoma; leukemia;
Breast carcinoma
Marrow depression;
mucosal inflammation
Route:
Inj
Bleomycin Testicular tumor;Squamous
cell carinoma; Hodgkin’s
lymphoma
Myelosuppression Chelates Cu/Fe
&produce
superoxide ions
&intercalate causing
chain scission,
Inhibits repair
Route:
Inj
Mitomycin C Cancers of stomach, cervix,
colon ,bladder
Marrow depression; Kills cells at G1-M
phase
Higly
toxic;
Inj

23. MISCILLANEOUS
1.Hydroxyurea:
MOA: Ribonucleotides Deoxy ribonucleotides
Ribonucleoside
diphosphate
reductase
S-phase specific
Use: Leukemia; Psoriasis; Polycythemia (Inc Hb
A.E: Myelosupression
Route: Oral
2. Procarbazine:
MOA: Depolymerizes DNA and cause chromosomal damage; Inhibits nucleic acid synthesis
• It is a weak MAO inhibitor
• Alcohol causes disulfiram like effects
Use: Hodgkin’s; Non-Hodgkin lymphoma; Oat cell carcinoma of lung
A.E: Leucopenia; Thrombocytopenia; Dermatitis

24. 3. Cisplatin:
• Bound to plasma proteins, slowly excreted
• Can also react with –SH groups
• Has radiomimetic poperty
Use: Metastatic testicular and ovarian
carcinoma
Route: Inj
A.E: Emetic; Renal impairment; Tinnitus;
Deafness;Hyperuricemia
4. L-Asparaginase:
A.E: Liver damage; Pancreatitis; allergy
Route: Inj

25. 5.Carboplatin:
Less reactive
Dose limiting toxicity-Thrombocytopenia
Less protein bound
Use: Ovarian , squamous, Lung carcinoma
6. Imatinib:
Inhibits tyrosine protein kinase; Ones that are
activated by platelet derived growth factor
A.E: Edema; Myalgia; Liver damage

26. GENERAL TOXICITY OF CYTOTOXIC DRUGS
Majority have effect on rapidly multiplying cells , affecting nucleic acid synthesis
Bone marrow:
Depression leads to granulocytopenia; thrombocytopenia; aplastic anemia
Infections and bleeding are usual complications
Lymhoreticular tissue:
Lymphocytopenia results in suppression of cell mediated immunity, damage to
epithelial tissue; so susceptibility to infections is increased.
Oral cavity:
Oral mucosa has high epithelial cell turnover, many drugs
produce stomatitis
Also subjected to breaches, trauma; Thrombocytopenia may
cause bleeding gums

27. GIT:
Diarrhea,shedding of mucosa, heamorrhages occur due to decrease in rate of
renewal of ucosal lining; Mucositis is common
Nausea,vomiting are common due to direct stimultion of CTZ
Skin:
Alopecia(due to damage to cells in hair follicles)
Dermatitis
Gonads:
Oligozoospermia and impotence in males
Inhibition of ovulation and amenorrhea in females
Foetus:
Abortion, foetal deth, teratogenesis

28. Carcinogenicity:
Secondary cancers , leukemia, lymphoma tumors appear with great frequency
after many years (Might be due to cell mediatd &humoral blockage)
Hyper uricaemia:
Massive desturction (Uric acid is byproduct of purine metabolism)
Inhibited by allopurinol

29. HORMONES
• Modify the growth of hormone-dependent tumors.
• All hormones are palliative
1. Glucocorticoids:
Mechanism: apoptosis is achieved via activation of death-inducing genes
or inhibiting the transcription of growth/survival genes.
Includes: Prednisolone; Dexamethasone
Marked lympholytic action
Use: Acute childhood leukemia; lymphoma; Breast cancer
Also used for controlling complications like hypercalcemia, hemolysis,
bleeding, Increased intracranial tension, edema
A.E: Hypercorticism(As doses given are v.high)

30. 2. Estrogen:
Physiological antagonists of androgens
Produce relief in prostate cancer, which is anrogen depndent tumor
Includes
• Fosfestrol:
Prodrug (Phosphatee derivative of stillbestrol)
Route: Oral,inj
• Selective estrogen receptor modulator(Tamoxifen):
• Aromatase Inhibitors:
Aromatase, turns the hormone androgen into estrogen in the body. This means that
less estrogen is available to stimulate the growth of hormone-receptor-positive breast
cancer cells
Includes letrazole

31. • Selective estrogen receptor down regulator (fulvestrant ):
Binds to estrogen receptor monomers, inhibits receptor dimerization,
translocation of receptor to the nucleus is reduced
degradation of the estrogen receptor is accelerated.
3. Anti-Androgen:
Includes flutamide, bicalutamide
Used in combination with orchiectomy(one or both testicles are removed)
MOA:
• Blocks the action of both endogenous and exogenous testosterone by
binding to the androgen receptor.
• Inhibitor of testosterone-stimulated
prostatic DNA synthesis.

32. 4. 5-alpha reucatse inhibitor:
• Includes finasteride and dutasteide
• Occasionally used
• Reduce size of prostate gland
5. GnRH agonists:
Indirectly inhibit estrogen/androgen secretion by suppressing FSH,LH release
Used in combination
6.Progestins:
inhibition of estradiol binding to its specific receptors,
inhibiting the formation of the estrogen-receptor system , the cause of cell growth
Use: Metastatic endometrial carcinoma, breast cancer

33. RESISTANCE TO ANTI CANCER DRUGS
It is primary(Present when drug is first given)
Acquired(developed during treatment with drug)
Various mechanisms:
• Drug Inactivation:
Many anticancer drugs must undergo metabolic activation in order to acquire clinical efficacy
EX: cytarabine (AraC), activated after multiple phosphorylation events. Down-regulation or
mutation in this pathway can produce a decrease in the activation and lead to drug
resistance
• Alteration of Drug Targets:
EX: certain anticancer drugs target topoisomerase II, mutations in this gene can confer resistance
• Decreased requirement of substrate
• Drug efflux
• Rapid repair of drug induced lesions
Reference:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190567/

34. RADIATION THERAPY
High energy rays are aimed at tumor cell, which damages DNA and destroys
ability to reproduce and finally eliminates
Used in 2ways-
• Radical: To cure cancer (Destroy tumors that haven't spread)
• Palliative: To reduce symptoms( shrink tumors, affecting quality of life )
Delivered 2 types:
External beam radiation (Ex: Proton, neutron beam therapy)
Internal radiation: (Brachytherapy)
Involves placing radioactive sources(Thin wires, capsules) inside patient.
Allows minimal radiation exposure to normal tissue.

35. FUTURE STRATEGIES
 Angiogenesis and metalloproteinase inhibitors
 Cyclo-oxygenase inhibitors
 p53 as anticancer target
 Antisense oligonucleotide
 Gene therapy
 Reversal of multi drug resistance

36. • RANG AND DALE’S Pharmacology page no.-718-733
• Essentials of medical pharmacology –by KD TRIPATHI page no.-819-834