A clear description of Cancer, causes, treatment and future stratergies

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