AT

Antineoplastic Pharmacology Lecture Notes

Antineoplastic Pharmacology Overview

  • Definition: Antineoplastic pharmacology involves the study of drugs that treat cancer by inhibiting the growth and spread of malignant cells.
  • Usage: Primarily used in chemotherapy, but also in conjunction with surgery, radiation therapy, and immunotherapy.

Cell Cycle Phases

  • Phases: The cell cycle comprises Interphase (G1, S, G2) and Mitosis.
    • G1 Phase: Cell growth and functioning; checks for DNA damage at G1 checkpoint.
    • S Phase: DNA replication happens.
    • G2 Phase: Further cell growth; checks for DNA damage before mitosis.
    • G0 Phase: Non-dividing state if issues are detected.
  • Importance in Cancer: Cancer cells frequently advance through the cell cycle without proper checkpoints.

Mechanisms Leading to Cancer

  1. Loss of Cell Cycle Checkpoints: Mutations in tumor suppressor genes (e.g., p53) inhibit cell cycle halting.
  2. Overactive Oncogenes: Mutated genes that promote uncontrolled cell division (e.g., RAS gene).
  3. Evading Apoptosis: Cancer cells can escape programmed cell death, allowing further mutation accumulation.

Apoptosis

  • Definition: Programmed cell death crucial to eliminate unnecessary or abnormal cells.
  • Features:
    • Cell shrinkage, chromatin condensation, nuclear fragmentation, membrane blebbing, and the formation of apoptotic bodies.

Antineoplastic Drugs

  • Classes of Antineoplastic Agents:
    1. DNA Alkylating Agents (e.g., Cyclophosphamide)
    2. Antimetabolites (e.g., Methotrexate, 5-Fluorouracil)
    3. Antitumor Antibiotics (e.g., Doxorubicin)
    4. Mitotic Inhibitors (e.g., Paclitaxel)
    5. Platinum-based Compounds (e.g., Cisplatin)
    6. Hormonal Agents (e.g., Tamoxifen, Leuprolide)
    7. Monoclonal Antibodies and Targeted Therapies
    8. Immunotherapy (e.g., Pembrolizumab)

DNA Alkylating Agents

  • Mechanism: Add alkyl groups to DNA, forming cross-links that prevent replication, leading to cell death.
  • Classification: Non-specific to the cell cycle; affect all phases, including G0.
  • Example: Cyclophosphamide is used for leukemias and solid tumors like breast cancer.
  • Side Effects: Aplastic anemia, risk of secondary malignancies, hair loss, gastrointestinal disturbances, teratogenic effects.

Platinum-based Compounds

  • Mechanism: Form cross-links between guanines in DNA, inhibiting DNA repair and replication.
  • Examples: Cisplatin is effective against various solid tumors like testicular and lung cancer.
  • Side Effects: Gastrointestinal disturbances (nausea/vomiting), nephrotoxicity, myelosuppression, ototoxicity.

Antimetabolites

  • Mechanism: Interfere with DNA/RNA synthesis, mimicking natural nucleotides. Key for treating leukemias, breast cancer, and intestinal tract cancers.
  • Examples: 5-Fluorouracil (5-FU) is effective during the S phase and often combined with leucovorin.
  • Side Effects: Bone marrow suppression, gastrointestinal disturbances, photosensitivity.

Antitumor Antibiotics

  • Example: Doxorubicin inhibits DNA replication by binding to topoisomerase II and forming free radicals.
  • Indications: Used for multiple cancers, including breast cancer and leukemias.
  • Side Effects: Cardiac toxicity, myelosuppression, alopecia, and others related to organ dysfunction.

Mitotic Inhibitors

  • Classes: Vinca alkaloids (e.g., Vincristine) prevent microtubule polymerization; Taxanes (e.g., Paclitaxel) stabilize microtubules.
  • Mechanism: Disrupts microtubule function essential for mitosis. Taxanes are active in M phase, while vinca alkaloids are specific to actively dividing cells.
  • Side Effects: Myelosuppression, neurotoxicity, alopecia.

Hormonal Antineoplastic Agents

  • Definition: Drugs targeting hormone-sensitive cancers by blocking hormonal signals.
  • Example: Tamoxifen, a selective estrogen receptor modulator used primarily for estrogen receptor-positive breast cancer.
  • Mechanism: Acts as an antagonist in breast tissue while behaving as an agonist in other tissues, leading to side effects such as hot flashes and endometrial changes.

Contraindications and Drug Interactions

  • General: Many antineoplastic drugs are contraindicated in pregnancy and during breastfeeding due to potential fetal harm.
  • Specific Drugs: Dosages and combinations require careful consideration of existing health conditions and potential interactions with medications like warfarin.