Principles of Cancer Pharmacology

Cell cycle kinetics, drug resistance, combination strategies, and supportive care

ATP = adenosine triphosphate  ·  BCL-2 = B-cell lymphoma 2 protein  ·  DNA = deoxyribonucleic acid  ·  G-CSF = granulocyte colony-stimulating factor  ·  G6PD = glucose-6-phosphate dehydrogenase  ·  MDR1 = multidrug resistance 1 gene  ·  NK-1 = neurokinin-1  ·  p53 = tumor protein 53

Cell Cycle & Drug Specificity
Cycle-Specific Agents
S-Phase and M-Phase Drugs
  • Antimetabolites: S-phase (methotrexate, 5-fluorouracil, cytarabine)
  • Vinca alkaloids: M-phase (vincristine, vinblastine)
  • Taxanes: M-phase (paclitaxel, docetaxel)
  • Log-kill plateau at high doses — schedule by prolonged infusion
  • G0 cells escape — quiescence confers resistance
Cycle-Nonspecific Agents
Alkylating Agents & Platinum Compounds
  • Kill cells regardless of cell cycle phase, including G0
  • Dose-response more nearly linear — dose escalation is meaningful
  • Nitrogen mustards, platinum compounds, nitrosoureas, busulfan
  • Antimetabolites also active in G0 via ribonucleic acid mechanisms at high doses
Log-Kill Hypothesis: Fraction Kill, Not Fixed Number
Initial burden
1010 cells (10 billion)
→
3-Log Kill
107 cells remain (99.9% killed)
→
Repeat Cycle
104 cells remain
→
Cure Requires
< 1 viable cell
Drug Resistance Mechanisms
Efflux
P-Glycoprotein
  • MDR1 gene product
  • Pumps anthracyclines, taxanes, vinca alkaloids out of cells
  • Adenosine triphosphate-dependent efflux
Target
Target Alteration
  • Dihydrofolate reductase amplification → methotrexate resistance
  • Loss of activating enzymes (deoxycytidine kinase, hypoxanthine-guanine phosphoribosyltransferase)
  • Topoisomerase II mutations
Apoptosis
BCL-2 & p53 Loss
  • p53 loss: no apoptosis signal after deoxyribonucleic acid damage
  • BCL-2 overexpression: sequesters pro-apoptotic proteins
  • Cells arrest but do not die → repair and proliferate
Combination Chemotherapy Principles
Principle Rationale Example
Non-overlapping toxicity Each drug can be given at full single-agent dose CHOP: cyclophosphamide (marrow), vincristine (nerve), doxorubicin (heart/marrow), prednisone (minimal marrow)
Non-cross-resistant mechanisms Reduces probability any one clone is resistant to all drugs BEP: platinum adducts + topoisomerase II inhibition + free radical strand breaks
Dose density Prevents tumor regrowth between cycles during exponential phase Dose-dense doxorubicin/cyclophosphamide/paclitaxel every 2 weeks with granulocyte colony-stimulating factor
Supportive Care: High-Yield Points
Antiemetics
Emetogenicity-Based Selection
  • High emetogenicity (cisplatin, carmustine, high-dose cyclophosphamide): serotonin type 3 antagonist + neurokinin-1 antagonist + dexamethasone
  • Moderate emetogenicity (carboplatin, doxorubicin, irinotecan): serotonin type 3 antagonist + dexamethasone
  • Acute: serotonin-mediated; delayed: substance P/neurokinin-1-mediated
Tumor Lysis Syndrome
Prevention & Rasburicase Safety
  • Hydration + allopurinol: standard prophylaxis
  • Rasburicase preferred in high-risk disease (Burkitt lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia)
  • Rasburicase absolutely contraindicated in glucose-6-phosphate dehydrogenase deficiency → severe hemolysis
  • Screen for glucose-6-phosphate dehydrogenase deficiency before rasburicase in at-risk patients
Clinical Safety Rule: Granulocyte Colony-Stimulating Factor Timing
Granulocyte colony-stimulating factor must not be started within 24 hours of chemotherapy administration. Starting it too early mobilizes proliferating neutrophil precursors that are vulnerable to cycle-specific cytotoxic agents still present in plasma, potentially worsening myelosuppression. The recommended window is 24 to 72 hours after the last dose of chemotherapy.