Principles of Cancer Chemotherapy

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).

⭐ 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.
  • 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.

⭐ 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.