anti-cancer drugs 3

Anti-Cancer Drugs

  • Traditional cancer chemotherapy targets DNA formation or replication via essential building blocks (purines and pyrimidines).

  • Most traditional anti-cancer drugs do not differentiate between neoplastic (cancer) and normal cells, affecting both.

  • Advances in molecular biology have led to the development of molecularly targeted drugs, such as:

    • Tyrosine Kinase Inhibitors

    • Monoclonal Antibodies

  • These new agents are still associated with severe and unpleasant side effects.

  • The rate of cancer cell proliferation affects tumor susceptibility to chemotherapy; rapidly dividing cells are more sensitive than slowly dividing cells.

Cell Cycle and Drug Classification

  • Resting State (Go)

  • Mitotic Phase (M)

    • G1 Phase: Cell growth before DNA synthesis.

    • S Phase: DNA synthesis.

    • G2 Phase: Preparation for mitosis.

Classification of Anti-Cancer Drugs

  • Cytotoxic Drugs

  • Hormonal Drugs

  • Molecularly Targeted Drugs

Cytotoxic Drugs

  • Kill cancer cells by preventing division and can be classified into:

    • Cell Cycle Specific Agents:

      1. Anti-metabolites (S-Phase)

      2. Topoisomerase II inhibitors (G1 - S phase)

      3. Topoisomerase I inhibitors (G2 - M phase)

      4. Taxanes (M-phase)

      5. Vinca alkaloids (M-phase)

      6. Anti-microtubule inhibitors (M-phase)

      7. Antitumor Antibiotics (G2–M phase)

    • Cell Cycle Non-Specific Agents:

      1. Antibiotics

      2. Alkylating agents

      3. Platinum analogs

Anti-Metabolites

  • Categories of Anti-Metabolites:

    • Folic Acid Analogues (Anti-folate)

    • Pyrimidine Analogues

    • Cytidine Analogues

    • Purine Analogues

Anti-Folates

  • Drugs:

    • Methotrexate (MTX) and Pemetrexed.

  • Mechanism of Action:

    • Inhibit dihydrofolate reductase (DHFR), disrupting purine ribonucleotide synthesis and inhibiting DNA replication.

  • Routes:

    • MTX: Intravenous (IV)/oral

    • Pemetrexed: IV infusion only.

  • Uses:

    • MTX: Breast cancer, head and neck cancer, non-Hodgkin’s lymphoma.

    • Pemetrexed: Mesothelioma and non-small cell lung cancer.

  • Adverse Effects:

    • Mucositis, myelosuppression, and thrombocytopenia.

Pyrimidine Analogues

  • 5-Fluorouracil (5-FU):

    • Mechanism: Inhibits thymidylate synthetase.

    • Route: IV

    • Uses: Gastric and colorectal, pancreatic, breast, and skin cancers.

    • Adverse Effects: Myelosuppression, mucositis, diarrhea, skin toxicity, neurotoxicity.

  • Capecitabine:

    • Oral fluoro-pyrimidine carbamate prodrug, metabolized to 5-FU.

    • Uses: Metastatic breast cancer in combination with other drugs.

Cytidine Analogues

  • Cytarabine (ara-C):

    • Mechanism: Converted to active metabolites inhibiting DNA polymerase α and β.

    • Route: IV infusion

    • Uses: Acute myeloblastic leukemia.

    • Adverse Effects: Myelosuppression, GIT disturbances, cerebellar ataxia.

  • Gemcitabine:

    • Mechanism: Inhibits ribonucleotide reductase and DNA polymerase, blocking DNA synthesis.

    • Route: IV infusion

    • Uses: Advanced pancreatic cancer, non-small cell lung carcinoma, bladder cancer.

Purine Analogues

  • 6-Mercaptopurine (6-MP):

    • Mechanism: Prodrug converted to TIMP, affecting DNA synthesis.

    • Route: Oral

    • Uses: Childhood acute leukemia.

    • Adverse Effects: Thrombocytopenia, GIT disturbance, hepatotoxicity, immunosuppression.

  • Fludarabine and Cladribine:

    • Effects on purine nucleotide biosynthesis and DNA formation.

Vinca Alkaloids

  • Mechanism: Inhibit tubulin polymerization, disrupting microtubule assembly and causing mitotic arrest.

  • Drugs:

    • Vinblastine: IV route, used for leukemias, lymphomas, and breast/lung cancers.

    • Vincristine: Similar to vinblastine but with different clinical activity and safety profile, used for Hodgkin’s lymphoma, neuroblastoma.

Taxanes and Topoisomerase Inhibitors

  • Paclitaxel and Docetaxel:

    • Mechanism: Disturb the microtubule and tubulin equilibrium.

    • Route: IV

    • Uses: Solid tumors (ovarian, advanced breast, lung, etc.).

    • Adverse Effects: Hypersensitivity, myelosuppression, peripheral neuropathy.

  • Topoisomerase I and II Inhibitors:

    • Irinotecan and Topotecan:** Target topoisomerase I, used in colorectal and ovarian cancers.

    • Etoposide and Teniposide: Inhibit topoisomerase II; used for testicular and lung cancers.

Alkylating Agents

  • Mechanisms include forming reactive carbonium ions that cross-link DNA and interrupt replication.

  • Classification:

    • Nitrogen mustards, Nitrosoureas, Alkyl sulfonates, Triazines, Ethylenimines.

Cyclophosphamide

  • Uses: CLL, soft tissue sarcoma, ovarian/breast cancer.

  • Adverse Effects: Myelosuppression, bladder toxicity, hemorrhagic cystitis.

Platinum Analogues

  • Mechanism: Formation of DNA-platinum adducts leading to apoptosis.

  • Uses: Various cancers, including head/neck, ovarian, and lung cancers.

Therapeutic Use of Carboplatin and Cisplatin

  • Carboplatin is an alternative for patients unable to tolerate cisplatin, both are effective against ovarian cancer.

  • Adverse Effects: Carboplatin is associated with less severe side effects than cisplatin, such as neurotoxicity and nephrotoxicity.

Hormonal Therapy for Breast Cancer

  • Tamoxifen: Oral route, blocks estrogen receptor in breast cancer.

  • Fluvestrant: IM route, induces degradation of the estrogen receptor.

  • Anastrozole: Oral route, aromatase inhibitor.

Hormonal Therapy for Prostate Cancer

  • Androgen-Deprecating Therapy: Includes Gn-RH agonists and androgen receptor blockers.

  • Cyproterone and Enzalutamide: used for metastatic prostate cancer.