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Principles of Chemotherapy, Immunotherapy and Targeted Therapy

Principles of Chemotherapy, Immunotherapy and Targeted Therapy

Principles of Chemotherapy, Immunotherapy and Targeted Therapy

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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. Cell cycle and chemotherapy drug targets

⭐ 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. Mechanisms of chemoresistanceoka

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.

Immune checkpoint inhibitors mechanism

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.

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