MANAGEMENT AND SCIENCE UNIVERSITY

Anticancer Chemotherapy
Dr. Rammohan

TRANSFORMING LIVES, ENRICHING FUTURE

 MANAGEMENT AND SCIENCE UNIVERSITY

Contents
1. Goals of cancer treatment
2. Cell Cycle and drugs acting on it
3. Log kill hypothesis
4. Combination treatment & Regimens
5. General adverse effects of anticancer drugs
6. Management of toxicities
7. Role of steroids in cancer treatment
8. Classification of anticancer drugs (MOA based)
9. MOA, Side effects and Clinical uses of some drugs

TRANSFORMING LIVES, ENRICHING FUTURE 2

 MANAGEMENT AND SCIENCE UNIVERSITY

TLO
• Describe classification of anticancer drugs (MOA based with
examples).
• Discuss the mechanism of action and adverse effects of
anticancer drugs.
• Describe the general adverse effects of anticancer drugs.
• Discuss the management of anticancer toxicities.
• Discuss the rationale of use of anticancer combinations.
• Discuss the rationale of steroids in cancer treatment.

TRANSFORMING LIVES, ENRICHING FUTURE 3

 MANAGEMENT AND SCIENCE UNIVERSITY

1. Goals of Cancer Treatment

1. Curative (Complete remission)
• Total eradication of cancer cells
• Curable cancers include testicular tumors, Wills tumor.

2. Palliative
• Alleviation of symptoms (↑ Quality of life; QOL)
• Avoidance of life-threatening toxicity
• Increased survival

TRANSFORMING LIVES, ENRICHING FUTURE 4

 MANAGEMENT AND SCIENCE UNIVERSITY

3. Adjuvant: chemotherapy given after surgery to eradicate

microscopic cancer and reduce the chance of cancers recurring
(prolonged remission) ex. breast cancer & colorectal cancer

4. Neo-adjuvant (Angiogenesis inhibitors): chemotherapy

given before surgery to shrink the tumor. This is to allow
the surgery to be more successful.

TRANSFORMING LIVES, ENRICHING FUTURE 5

 MANAGEMENT AND SCIENCE UNIVERSITY

2. Goals of Cancer Treatment

TRANSFORMING LIVES, ENRICHING FUTURE 6

 MANAGEMENT AND SCIENCE UNIVERSITY

• Growth fraction - The ratio of proliferating cells to cells in resting phase

(G0), is called the growth fraction.

• A tissue with a large percentage of proliferating cells & few cells in G0

has a high growth fraction (CML, lymphomas and Hodgkin’s disease).

• A tissue composed of mostly of cells in G0 has a low growth fraction

(solid tumours ex. breast cancer).

TRANSFORMING LIVES, ENRICHING FUTURE 7

 MANAGEMENT AND SCIENCE UNIVERSITY

3. Log kill hypothesis

• According to the log-kill hypothesis, chemotherapeutic agents kill a constant
fraction of cells (first order kinetics), rather than a specific number of cells, after
each dose of a particular drug.

1. Solid tumors - generally have a low growth fraction thus respond poorly to
chemotherapy & in most cases need to be removed by surgery.
2. Disseminated cancers- generally have a high growth fraction & generally respond
well to chemotherapy.

For example, assuming a 99% kill per cycle of chemotherapy, a tumor of 1010 cells
would be reduced to 1 cell with 5 treatment cycles. However, the tumor can also
re-grow during the intervals between treatments, limiting the net reduction of
each fractional kill.

TRANSFORMING LIVES, ENRICHING FUTURE 8

 MANAGEMENT AND SCIENCE UNIVERSITY

TRANSFORMING LIVES, ENRICHING FUTURE 9

 MANAGEMENT AND SCIENCE UNIVERSITY

Example
1x 1010 cells (clinically detectable cancer)
Cycle 1
1x 108 cells
Cycle 2 each cycle of chemotherapy kills 99% cells (2
1x 106 cells log kill)
Cycle 3
1x 104 cells
Cycle 4
1x 102 cells
Cycle 5
1 cell
TRANSFORMING LIVES, ENRICHING FUTURE 10
 MANAGEMENT AND SCIENCE UNIVERSITY

TRANSFORMING LIVES, ENRICHING FUTURE 11

 MANAGEMENT AND SCIENCE UNIVERSITY

4. Combination Chemotherapy
Combinations of agents with differing toxicities & mechanisms of action are
often employed to overcome the limited cell kill of individual anti cancer agents.
Each drug selected should be effective alone.

3 advantages of combination therapy:

1. Suppression of drug resistance - less chance of a cell developing resistance to 2
drugs than to 1 drug.
2. Increased cancer cell kill - administration of drugs with different mechanisms
of action.
3. Reduced injury to normal cells - by using a combination of drugs that do not
have overlapping toxicities, we can achieve a greater anticancer effect than we
could by using any one agent alone.

TRANSFORMING LIVES, ENRICHING FUTURE 12

 MANAGEMENT AND SCIENCE UNIVERSITY

Combination Regimens
ABVD (Hodgkin’s Lymphoma): adriamycin (doxorubicin), bleomycin, vinblastine,
dacarbazine.

FOL F OX (colorectal cancer): (FOL:folinic acid/leucovorin); (F: 5-fluorouracil;) (Ox:

Oxaliplatin).

FOL F IRI (colorectal cancer): (FOL:folinic acid/leucovorin); (F: 5-fluorouracil;)

(IRI:irinotecan)

CMF (breast cancer): cyclophosphamide-MTX-fluorouracil

TRANSFORMING LIVES, ENRICHING FUTURE 13
 MANAGEMENT AND SCIENCE UNIVERSITY

5. General adverse effects of anti cancer drugs

• Most of them are antiproliferative, i.e. they damage DNA
and so initiate apoptosis.

• They also affect rapidly dividing normal cells (GIT, bone

marrow, hair follicles, sperm cells and ova).

• Toxicities are exhibited by all anticancer drugs.

TRANSFORMING LIVES, ENRICHING FUTURE 14

 MANAGEMENT AND SCIENCE UNIVERSITY

General Adverse effects of Anticancer Drugs

Tissue Undesirable Effects
Bone marrow Leukopenia and resulting infections
Immunosuppression
Thrombocytopenia

Anemia
GI tract Oral or intestinal ulceration
Diarrhea
Hair follicles Alopecia
Gonads Menstrual irregularities, including premature
menarche; impaired spermatogenesis
Wounds Impaired healing
Fetus Teratogenesis (especially during first trimester)

TRANSFORMING LIVES, ENRICHING FUTURE 15

 MANAGEMENT AND SCIENCE UNIVERSITY

6. Management of toxicities
Supportive treatment
Nausea and vomiting : 5-HT3 antagonists (ondansetron)
Cancer cachexia: glucocorticoids
Hyperuricemia: Allopurinol
Hypercalcemia (TLS): Alendronate (Bisphosphonates)
Bone marrow suppression : Filgrastim, Sargramostim (colony stimulating factors).
Specific drug toxicity
MTX toxicity : Leucovorin
Cyclophosphamide toxicity : Mesna
Anthracycline-induced cardiotoxicity: Dexrazoxane
Cisplatin-induced nephrotoxicity: Amifostine
TRANSFORMING LIVES, ENRICHING FUTURE 16
 MANAGEMENT AND SCIENCE UNIVERSITY

7. Role of steroids in cancer treatment

1.Anti-inflammatory effect
2. Increases appetite
3. Produce euphoria (feeling of well being)
4. Increases body weight
5. Prevents hypersensitivity reactions
6. Treatment of Hypercalcemia (Paraneoplastic syndrome)
7. Increase the antiemetic effect

TRANSFORMING LIVES, ENRICHING FUTURE 17

 MANAGEMENT AND SCIENCE UNIVERSITY

8. Classification based on MOA

i. Cell cycle nonspecific agents (CCNS): effective for low growth
fraction cancers. Ex. Solid tumours and high growth fraction cancers
Ex. Haematological cancers. acts on both dividing and resting cells.

A. Alkylating agents: busulfan, chlorambucil, cyclophosphamide,

dacarbazine, carmustine, lomustine, melphalan, cisplatin,
carboplatin, oxaliplatin

B. Anthracyclines: daunorubicin, doxorubicin, epirubicin,

idarubicin,

antibiotics: D-actinomycin, mitomycin

TRANSFORMING LIVES, ENRICHING FUTURE 18

 MANAGEMENT AND SCIENCE UNIVERSITY

ii. Cell cycle specific agents (CCS): effective for high growth fraction cancers. Ex.
Haematological cancers
i. Antimetabolites (S phase): FA analogs: methotrexate, pemetrexed, trimetrexate,
purine analogs: 6-mercaptopurine, 6-thioguanine, fludarabine, cladrabine, pyrimidine
analogs: 5-fluorouracil, gemcitabine, capecitabine, cytarabine.

ii. Vinca alkaloids (M phase): vinblastine, vincristine, vinorelbine.

iii. Podophyllotoxin (G-S Phase): etoposide, teniposide

iv. Camptothecins (G-S Phase) : topotecan, irinotecan.

v. Taxanes (M phase): paclitaxel, docetaxel, ixabepilone

vi. Antitumour antibiotics (G-M Phase): bleomycin

TRANSFORMING LIVES, ENRICHING FUTURE 19

 MANAGEMENT AND SCIENCE UNIVERSITY

9. MOA, Side effects and Clinical Uses of some drugs:

i. Cell cycle Non-specific drugs:
A. Alkylating agent-like Platinum compounds (Cisplatin):
• MOA: carbonium ions alkylate and attack the N7 nucleophilic center on
guanine base of DNA, resulting in crosslinking /abnormal base pairing/
scission of DNA strands and block replication and transcription (cytotoxicity).

• Side effects: Nausea and vomiting (highly emetogenic), nephrotoxicity (dose-

limiting), neurotoxicity (sensory loss, numbness, tingling, pain, and burning
sensation), Bone marrow suppression, ototoxicity, hypomagnesaemia,
hypokalaemia and hypocalcaemia.

• Clinical Uses: lung cancer, ovarian cancer, breast cancer.

TRANSFORMING LIVES, ENRICHING FUTURE 20

 MANAGEMENT AND SCIENCE UNIVERSITY

B. Anthracyclines (Doxorubicin)
MOA: These drugs intercalate between base pairs,
inhibit topoisomerase II and also generate free radicals.
Block RNA and DNA synthesis and cause strand scission.

 Used as a component in ABVD regimen in Hodgkin’s

lymphoma.

 Side effects: Cardiac toxicity

(arrthythmias, ECG changes, pericarditis, myocarditis,
Dilated cardiomyopathy, CHF), BMS, alopecia
Radiation recall reaction (dermatitis, mucositis,
pneumonitis, myositis)

TRANSFORMING LIVES, ENRICHING FUTURE 21

 MANAGEMENT AND SCIENCE UNIVERSITY

ii. Cell Cycle Specific Drugs

A. Antimetabolites
• They are structurally similar to endogenous compounds.
• Act as antagonists of:
• Folic acid (methotrexate)
• Purines (6-MP)
• Pyrimidine (5-FU

TRANSFORMING LIVES, ENRICHING FUTURE 22

 MANAGEMENT AND SCIENCE UNIVERSITY

i. Methotrexate:
MTX is a folic acid analog that binds with high affinity to dihydrofolate reductase
enzyme (DHFR), interferes with synthesis of tetrahydrofolate (THF). THF serves as
the key one-carbon carrier for enzymatic processes involved in de novo synthesis
of thymidylate, purine nucleotides, and the amino acids serine and methionine.
Inhibition of formation of DNA, RNA, and key cellular proteins. (S phase specific).
 used alone or in combination in the treatment of breast cancer, epidermoid
cancers, lung cancer, advanced stage NHL.

 Side effects: nausea, hepatotoxicity, ulcerative stomatitis, BMS (leukopenia,

predisposition to infection), acute pneumonitis, kidney failure, Folic acid
deficiency.
 Uses: Disease-modifying treatment like RA, psoriasis, lupus, Crohn's disease,
eczema and many forms of vasculitis.

TRANSFORMING LIVES, ENRICHING FUTURE 23

 MANAGEMENT AND SCIENCE UNIVERSITY

ii. 5-Fluorouracil: thymidylate synthase (TS) inhibitor.

MOA: InhibitsTS, blocks synthesis of the pyrimidine thymidine, a nucleoside
required for DNA replication.
Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) to
form thymidine monophosphate (dTMP).
Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous
cells undergo ‘thymineless’ death.

Uses: Metastatic carcinomas of the breast and the GI tract, Carcinomas of the
ovary, cervix, urinary bladder, prostate, pancreas, and oropharyngeal cancer.

Side effects: nausea, mucositis, diarrhea, hand and foot syndrome, alopecia,
hyperpigmentation, neurologic deficits, BMS.

TRANSFORMING LIVES, ENRICHING FUTURE 24

 MANAGEMENT AND SCIENCE UNIVERSITY

B. Plant alkaloids:
i. Vinca alkaloids (M-phase): Vinblastine, vincristine, vinorelbine.
ii. Podophyllotoxins: Etoposide, teniposide.
iii. Camptothecins: Topotecan, irinotecan
iv. Taxanes: Paclitaxel, Docetaxel

i. Vinblastine: Microtubule Synthesis /spindle poison (M-phase)

MOA: These drugs block the formation of mitotic spindle by preventing the
assembly of tubulin dimers into microtubules. (block polymerization).
Side effects: GI upset, alopecia, leucopenia, thrombocytopenia, sweating, muscle
cramps.
Uses: component of ABVD regimen (Hodgkin’s Lymphoma), NSLC, Bladder cancer,
testicular cancer
TRANSFORMING LIVES, ENRICHING FUTURE 25
 MANAGEMENT AND SCIENCE UNIVERSITY

Side effects: Neurotoxicity

(Paresthesias, Loss of
reflexes, Foot drop, Ataxia).

Uses: ABVD regimen

Hodgkin’s disease,
Lymphomas
Carcinoma breast
Testicular tumors

TRANSFORMING LIVES, ENRICHING FUTURE 26

 MANAGEMENT AND SCIENCE UNIVERSITY

iv. Taxanes  These drugs act by interfering with mitotic

spindle.

 They prevent conversion of microtubule

polymer into tubulin monomers (M-phase)
and interfere with microtubule/spindle formation.

Side effects: Neutropenia, Peripheral neuropathy.

Uses: first and second line in ovarian cancer.

breast and NSCLC, bladder, prostate,
esophageal cancers.

TRANSFORMING LIVES, ENRICHING FUTURE 27

 MANAGEMENT AND SCIENCE UNIVERSITY

Q&A
A 32-year-old woman was given antineoplastic drug regimen, post surgery for
breast tumor. The regimen consisted of doxorubicin followed by methotrexate
and fluorouracil.
1. Which of the following, best describes the mechanism of anticancer action of
fluorouracil?
(A) Cross-linking of double-stranded DNA
(B) Mitotic poison
(C) Interference with the activity of topoisomerases II
(D) Irreversible inhibition of thymidylate synthase
(E) Inhibition of dihydrofolate reductase

TRANSFORMING LIVES, ENRICHING FUTURE 28

 MANAGEMENT AND SCIENCE UNIVERSITY

After several cycles of chemotherapy, the patient was found to have a high resting
heart rate. A noninvasive radionuclide scan revealed evidence of cardiomyopathy.

2. The drug that is most likely responsible is

(A) Tamoxifen
(B) Doxorubicin
(C) Fluorouracil
(D) Methotrexate
(E) Paclitaxel

TRANSFORMING LIVES, ENRICHING FUTURE 29

 MANAGEMENT AND SCIENCE UNIVERSITY

Thank you for your attention

TRANSFORMING LIVES, ENRICHING FUTURE 30