Principles of Cancer Chemotherapy

Principles of Cancer Chemotherapy

Principles of Cancer Chemotherapy

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Cell Cycle - Cancer's Clockwork

  • Phases & Key Events:
    • G0: Quiescent/Resting.
    • G1: Growth, protein/RNA synth. G1/S checkpoint (p53).
    • S: DNA synthesis.
    • G2: Pre-mitotic growth. G2/M checkpoint.
    • M: Mitosis (Prophase, Metaphase, Anaphase, Telophase).
  • Drug Classification:
    • Cell Cycle Specific (CCS): Target specific phases.
      • S-phase: Antimetabolites (Methotrexate, 5-FU), Etoposide.
      • M-phase: Vinca alkaloids (Vincristine), Taxanes (Paclitaxel). 📌 Microtubules Targeted in M-phase.
      • G2-phase: Bleomycin.
    • Cell Cycle Non-Specific (CCNS): Act on all phases (incl. G0). E.g., Alkylating agents, Cisplatin.
  • Log-Kill Hypothesis: Kills constant fraction of cells/cycle (e.g., 3-log kill: $10^{12} \rightarrow 10^9$ cells). Cancer cell cycle phases and chemotherapy strategies

⭐ Most human solid tumors have a low growth fraction, making them more sensitive to CCNS drugs or requiring recruitment strategies for CCS drugs.

Treatment Aims - Strategic Strikes

  • Primary Goals of Chemotherapy:

    • Cure: Complete eradication of all neoplastic cells.
      • Possible in select cancers (e.g., testicular, Hodgkin's, ALL, choriocarcinoma).
    • Control: Prevent further tumor growth and spread when cure is unlikely.
      • Aims to prolong survival and maintain patient's Quality of Life (QoL).
    • Palliation: Alleviate symptoms (e.g., pain, obstruction) and improve QoL in advanced, incurable cancers.
  • Key Therapeutic Strategies & Timing:

Gompertzian Growth Model: Tumor growth fraction is highest when small, decreasing as tumor enlarges. Chemotherapy is most effective against rapidly dividing cells (high growth fraction), explaining why smaller tumors/micrometastases are more chemosensitive.

Drug Resistance - Cancer's Defenses

  • Types:
    • Primary (Intrinsic): No prior drug exposure.
    • Acquired: Develops post-exposure.
  • Mechanisms:
    • ↓ Drug influx/uptake (e.g., methotrexate).
    • ↑ Drug efflux: P-glycoprotein (MDR1 gene) pumps drugs out. 📌 MDR1: Many Drugs Removed. P-glycoprotein efflux pump mechanism and inhibition
    • Altered drug targets (e.g., enzyme mutation, gene amplification).
    • ↑ Drug inactivation (e.g., glutathione conjugation).
    • ↓ Drug activation (pro-drugs not converted).
    • ↑ DNA repair mechanisms.
    • Evasion of apoptosis (e.g., p53 mutation, ↑Bcl-2).
  • Multidrug Resistance (MDR): Cross-resistance to multiple, structurally unrelated drugs.

    ⭐ P-glycoprotein (encoded by ABCB1 or MDR1 gene) is a major cause of MDR, effluxing natural product drugs like anthracyclines, vinca alkaloids, and taxanes.

  • Overcoming Resistance:
    • Combination chemotherapy.
    • High-dose therapy + rescue (e.g., Leucovorin for Methotrexate).
    • MDR modulators (e.g., verapamil; limited by toxicity).
    • Targeted therapies bypassing resistance mechanisms.

Side Effects - Battle Scars

  • Common (Rapidly Dividing Cells):
    • GIT: Nausea, vomiting (CTZ), mucositis, diarrhea.
    • Bone Marrow Suppression (BMS):
      • Neutropenia (ANC < 500/µL ↑infection risk).
      • Thrombocytopenia (↑bleeding).
      • Anemia.
    • Alopecia.
    • Gonadal dysfunction: Infertility.
  • Key Organ-Specific Toxicities:
    • Cardio: Doxorubicin (cumulative; Dexrazoxane).
    • Nephro: Cisplatin (hydrate, amifostine), Methotrexate (high dose).
    • Neuro: Vincristine (peripheral), Cisplatin (ototoxicity, peripheral).
    • Pulmonary: Bleomycin, Busulfan.
    • Hemorrhagic Cystitis: Cyclophosphamide/Ifosfamide (Acrolein metabolite; MESNA, hydration). 📌 "MESNA for Cyclo's Bladder"
  • Tumor Lysis Syndrome (TLS):
    • Lab: ↑K⁺, ↑PO₄³⁻, ↑Uric acid, ↓Ca²⁺.
    • Manage: Hydration, allopurinol/rasburicase. Chemotherapy Side Effects by Body System

⭐ Cisplatin: major dose-limiting toxicities are nephrotoxicity and ototoxicity. Amifostine & hydration for nephroprotection.

High‑Yield Points - ⚡ Biggest Takeaways

  • Cell cycle-specific (CCS) drugs (e.g., antimetabolites, vincas) target dividing cells; CCNS drugs act on all cells.
  • Log-kill hypothesis: Chemotherapy kills a constant fraction of tumor cells per cycle.
  • Combination therapy is key: ↑ efficacy, ↓ resistance, manages toxicity, targets heterogeneity.
  • Drug resistance mechanisms: P-glycoprotein efflux, altered targets, ↑ DNA repair, ↓ drug activation.
  • Major dose-limiting toxicities: myelosuppression, mucositis, nausea/vomiting.
  • Sanctuary sites (e.g., CNS, testes) hinder drug penetration and efficacy.

Practice Questions: Principles of Cancer Chemotherapy

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Flashcards: Principles of Cancer Chemotherapy

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Present chemotherapy regimen used for breast cancer is ACT, i.e., _____, Cyclophosphamide, and Taxane (Paclitaxel)

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Present chemotherapy regimen used for breast cancer is ACT, i.e., _____, Cyclophosphamide, and Taxane (Paclitaxel)

Adriamycin

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