Antineoplastic Agents: Mechanism of Action, Therapeutic uses, adverse effect and drug interactions

 ANTINEOPLASTIC AGENTS

1. Classification of Antineoplastic Drugs

A. Alkylating Agents
Cyclophosphamide, Chlorambucil, Dacarbazine

B. Antimetabolites
Methotrexate, 6-Mercaptopurine, 5-Fluorouracil

C. Mitotic Inhibitors

• Vinca alkaloids: Vincristine, Vinblastine
• Taxanes: Paclitaxel

D. Antitumor Antibiotics
Actinomycin D, Doxorubicin, Daunorubicin, Bleomycin

E. Miscellaneous Agents
L-Asparaginase, Cisplatin, Carboplatin, Etoposide

2. General Principles of Cancer Management

• Early detection and accurate diagnosis are essential.
• Combination chemotherapy is preferred to prevent resistance.
• Adequate rest periods reduce toxicity and allow normal tissue recovery.
• Supportive therapy (antiemetics, hydration, growth factors) is important.
• Individualize dose based on tumor type and patient tolerance.

3. Individual Drugs

3.1 Alkylating Agents

Cyclophosphamide

MOA

·       Prodrug activated in the liver to form phosphoramide mustard.

·       The active metabolite alkylates DNA at the N7 position of guanine.

·       Causes cross-linking of DNA strands, inhibiting replication and transcription.

·       Leads to apoptosis of rapidly dividing cancer cells.

Therapeutic Uses: Breast cancer, lymphoma, leukemia.
Adverse Effects: Myelosuppression, hemorrhagic cystitis, alopecia.
Drug Interactions: Increased toxicity with allopurinol; additive marrow suppression with other cytotoxics.

Chlorambucil

MOA:

·       Forms reactive ethyleniminium ions.

·       These ions alkylate DNA bases.

·       Prevents DNA strand separation and replication.

·       Induces cell-cycle arrest and cell death.

Therapeutic Uses: Chronic lymphocytic leukemia, Hodgkin’s disease.
Adverse Effects: Bone marrow suppression, sterility, GI upset.
Drug Interactions: Additive toxicity with radiation or other cytotoxics.

Dacarbazine

MOA:

·       Activated by hepatic microsomal enzymes.

·       Forms methyl carbonium ions that methylate DNA.

·       Inhibits DNA synthesis by strand breakage.

·       Triggers apoptosis in tumor cells.

Therapeutic Uses: Malignant melanoma, Hodgkin’s lymphoma.
Adverse Effects: Nausea, vomiting, myelosuppression.
Drug Interactions: Avoid alcohol; interacts with hepatotoxic drugs.

3.2 Antimetabolites

Methotrexate

MOA:

·       Competitively inhibits dihydrofolate reductase (DHFR).

·       Decreases tetrahydrofolate formation.

·       Blocks thymidylate and purine synthesis.

·       Prevents DNA replication and cell division.

Therapeutic Uses: Leukemia, choriocarcinoma, rheumatoid arthritis (low dose).
Adverse Effects: Bone marrow suppression, mucositis, hepatotoxicity.
Drug Interactions: Increased toxicity with NSAIDs, sulfonamides, phenytoin.

6-Mercaptopurine

MOA:

·       Converted to thio-IMP by HGPRT enzyme.

·       Inhibits de novo purine synthesis.

·       Blocks DNA and RNA formation.

·       Induces cytotoxicity in rapidly dividing cells.

Therapeutic Uses: Acute lymphoblastic leukemia.
Adverse Effects: Myelosuppression, hepatotoxicity.
Drug Interactions: Dose reduced with allopurinol (xanthine oxidase inhibitor).

5-Fluorouracil (5-FU)

MOA:

·       Converted to FdUMP inside cells.

·       FdUMP binds and inhibits thymidylate synthase.

·       Depletes thymidine pool required for DNA synthesis.

·       Causes “thymineless death” in proliferating cells.

Therapeutic Uses: Colon, breast, gastric cancers.
Adverse Effects: Myelosuppression, diarrhea, hand-foot syndrome.
Drug Interactions: Leucovorin enhances efficacy; additive toxicity with other myelosuppressants.

3.3 Vinca Alkaloids

Vincristine

MOA:

·       Binds to tubulin dimers.

·       Prevents microtubule polymerization.

·       Arrests cells in metaphase.

·       Leads to apoptosis of mitotic cells.

Therapeutic Uses: Leukemias, lymphomas, pediatric solid tumors.
Adverse Effects: Peripheral neuropathy, constipation, mild myelosuppression.
Drug Interactions: Additive neurotoxicity with isoniazid or phenytoin.

Vinblastine

MOA:

·       Binds to tubulin.

·       Inhibits spindle formation.

·       Arrests mitosis in metaphase.

·       Induces cell death.

Therapeutic Uses: Hodgkin’s disease, testicular carcinoma.
Adverse Effects: Myelosuppression, GI upset, alopecia.
Drug Interactions: Additive marrow suppression with other cytotoxics.

3.4 Taxanes

Paclitaxel

MOA:

·       Promotes abnormal polymerization of tubulin.

·       Prevents microtubule depolymerization.

·       Blocks mitotic spindle disassembly.

·       Arrests cell division at G2/M phase.

Therapeutic Uses: Ovarian, breast, lung cancers.
Adverse Effects: Myelosuppression, neuropathy, hypersensitivity reactions.
Drug Interactions: Enhanced toxicity with cisplatin; metabolized by CYP3A4.

3.5 Antitumor Antibiotics

Actinomycin D

MOA:

·       Intercalates between DNA base pairs.

·       Blocks RNA polymerase movement.

·       Inhibits transcription and DNA synthesis.

·       Leads to apoptosis.

Therapeutic Uses: Wilms’ tumor, rhabdomyosarcoma.
Adverse Effects: Bone marrow suppression, mucositis.
Drug Interactions: Additive myelosuppression with other agents.

Doxorubicin & Daunorubicin

MOA:

·       Intercalate between DNA strands.

·       Inhibit topoisomerase II enzyme.

·       Generate free radicals causing strand breaks.

·       Disrupt replication and trigger apoptosis.

Therapeutic Uses: Doxorubicin—solid tumors, breast cancer; Daunorubicin—leukemia.
Adverse Effects: Cardiotoxicity, alopecia, myelosuppression.
Drug Interactions: Avoid with other cardiotoxic drugs (e.g., trastuzumab).

Bleomycin

MOA:

·       Binds to DNA and chelates metal ions.

·       Generates free radicals causing strand breaks.

·       Arrests cell cycle at G2 phase.

·       Induces apoptosis.

Therapeutic Uses: Testicular cancer, Hodgkin’s lymphoma.
Adverse Effects: Pulmonary fibrosis, skin hyperpigmentation.
Drug Interactions: Increased lung toxicity with oxygen or G-CSF.

3.6 Miscellaneous Agents

L-Asparaginase

MOA:

·       Hydrolyzes L-asparagine to aspartic acid and ammonia.

·       Depletes extracellular asparagine supply.

·       Tumor cells lacking asparagine synthetase cannot synthesize protein.

·       Results in inhibition of tumor cell growth.

Therapeutic Uses: Acute lymphoblastic leukemia.
Adverse Effects: Hypersensitivity, pancreatitis, liver dysfunction.
Drug Interactions: Antagonistic with methotrexate.

Cisplatin / Carboplatin

MOA:

·       Form covalent bonds with DNA bases.

·       Produce intra- and inter-strand cross-links.

·       Distort DNA structure and inhibit replication.

·       Induce apoptosis.

Therapeutic Uses: Testicular, ovarian, bladder cancers.
Adverse Effects: Nephrotoxicity, ototoxicity, nausea, vomiting.
Drug Interactions: Increased nephrotoxicity with aminoglycosides or furosemide.

Etoposide

MOA:

·       Inhibits topoisomerase II enzyme.

·       Prevents re-ligation of DNA strands.

·       Accumulation of DNA breaks leads to cell cycle arrest at G2 phase.

·       Triggers apoptosis.

Therapeutic Uses: Small cell lung cancer, testicular cancer.
Adverse Effects: Myelosuppression, alopecia, hypotension.
Drug Interactions: Enhanced toxicity with cisplatin or warfarin.

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