Principles of Chemotherapy, Immunotherapy and Targeted Therapy

Chemotherapy Principles - Cell Cycle Killers

• Cell Cycle Specific (CCS) Agents: Exert cytotoxic effects during specific phases of the cell cycle. Most effective against high growth fraction tumors.
  • G1 Phase (Presynthetic Growth):
    • L-Asparaginase: Depletes asparagine.
    • Corticosteroids: Lympholytic.
  • S Phase (DNA Synthesis): 📌 Suspect AntiMetabolites, Hydroxyurea, Irinotecan, Topotecan.
    • Antimetabolites: Methotrexate (MTX), 5-Fluorouracil (5-FU), Cytarabine (Ara-C).
    • Hydroxyurea: Inhibits ribonucleotide reductase.
    • Topoisomerase I inhibitors: Irinotecan, Topotecan.
  • G2 Phase (Premitotic Growth & DNA Repair):
    • Bleomycin: Causes DNA strand breaks.
    • Etoposide, Teniposide: Inhibit Topoisomerase II.
  • M Phase (Mitosis - Microtubule Targets):
    • Vinca Alkaloids (e.g., Vincristine, Vinblastine): Inhibit microtubule polymerization.
    • Taxanes (e.g., Paclitaxel, Docetaxel): Stabilize microtubules.

⭐ Vincristine is known for its neurotoxicity (peripheral neuropathy) and is typically dose-capped, while Vinblastine is more myelosuppressive.

Chemo Toxicities & Resistance - Toxic Turmoil

• General Toxicities
  • Myelosuppression: Nadir 7-14 days.
    • Neutropenia (ANC < 1500/µL; Febrile if fever > 38.3°C + ANC < 500/µL)
    • Anemia
    • Thrombocytopenia
  • Nausea/Vomiting (N/V): Ondansetron, Aprepitant.
  • Mucositis, Alopecia, Fatigue.
• Key Organ Toxicities
  • Doxorubicin: Cardiotoxicity (max 450-550 mg/m²; Dexrazoxane).
  • Trastuzumab: Cardiotoxicity.
  • Bleomycin: Pulmonary fibrosis.
  • Methotrexate (MTX): Pneumonitis, Nephrotoxicity (crystalluria; alkalinize urine), Mucositis.
  • Cisplatin: Nephrotoxicity (ATN; Amifostine, hydration), Ototoxicity, Peripheral neuropathy.
  • Vinca alkaloids: Peripheral neuropathy.
  • Taxanes: Peripheral neuropathy.
  • Cyclophosphamide/Ifosfamide: Hemorrhagic cystitis (Acrolein; MESNA).
• Chemoresistance
  • Mechanisms: ↑Efflux (P-glycoprotein/MDR1), ↓Uptake, Drug inactivation, Target alteration (mutations), ↑DNA repair, Apoptosis evasion.

⭐ P-glycoprotein (MDR1 gene product) is a major mechanism of multi-drug resistance, actively pumping chemo drugs out of cancer cells. oka

Immunotherapy Principles - Immune System Unleashed

• Core: Enhances body's immune system to fight cancer.
• Mechanisms:
  • Immune Checkpoint Inhibitors (ICIs): Release T-cell "brakes".
    • CTLA-4 inh. (Ipilimumab): Early T-cell priming (lymph node).
    • PD-1 inh. (Nivolumab, Pembrolizumab): Act on T-cells in TME.
    • PD-L1 inh. (Atezolizumab): Target ligand on tumor/immune cells (TME).
  • Adoptive Cell Therapy (ACT):
    • CAR T-cells: Engineered T-cells (Chimeric Antigen Receptors) target tumor antigens (e.g., CD19).
  • Monoclonal Abs (mAbs): Target tumor antigens (Rituximab-CD20); opsonization, ADCC.
• Immune-Related Adverse Events (irAEs):
  • Overactive immunity: Dermatitis, colitis, hepatitis, pneumonitis, endocrinopathies (hypophysitis, thyroiditis).
  • Manage: Corticosteroids, therapy interruption/discontinuation.

⭐ > Ipilimumab (anti-CTLA-4) was the first ICI to show survival benefit in metastatic melanoma.

Targeted Therapy Principles - Precision Strikes

• Precision medicine: Exploits specific molecular alterations in cancer cells.
• Requires biomarker identification (e.g., EGFR, HER2, BRAF, ALK, PD-L1).
• Often cytostatic; side effects target-dependent (e.g., EGFR inhibitor rash).
• Key types:
  • Monoclonal Antibodies (mAbs): "-mab" suffix.
    • Target extracellular/surface molecules (e.g., Trastuzumab for HER2).
    • Mechanisms: ADCC, CDC, direct signaling block, payload delivery (ADCs).
  • Small Molecule Inhibitors (SMIs/TKIs): "-nib" suffix.
    • Target intracellular kinases/pathways (e.g., Imatinib for BCR-ABL).
• Resistance can develop via target mutation or pathway bypass.

⭐ Trastuzumab (Herceptin) targets HER2 receptor; essential for HER2-positive breast cancer and gastric cancer treatment regimens where HER2 is overexpressed/amplified.

High‑Yield Points - ⚡ Biggest Takeaways

• CCS drugs target specific cell cycle phases; CCNS drugs act phase-independently.
• Nadir (lowest blood counts) typically 7-14 days post-chemo; risk of infection.
• Tumor Lysis Syndrome (TLS): ↑K⁺, ↑PO₄³⁻, ↑Uric acid, ↓Ca²⁺. Manage with hydration, Allopurinol/Rasburicase.
• Checkpoint Inhibitors (PD-1, CTLA-4) cause immune-related Adverse Events (irAEs).
• Targeted Therapy: MAbs (Rituximab-CD20, Trastuzumab-HER2) & TKIs (Imatinib-BCR-ABL).
• Febrile Neutropenia (ANC < 500/µL + fever): oncologic emergency, immediate antibiotics.