Chapter 38: Pharmacology and Toxicity of Antineoplastic Drugs

BASIC PRINCIPLES OF CANCER CHEMOTHERAPY

• Knowledge of drug actions, clinical toxicities, pharmacokinetics, and drug interactions is essential for the safe and effective administration of cancer chemotherapy.

• Base treatment on evidence from clinical trials.

• Use established regimens and recheck doses.

• Choice of a particular drug treatment program should depend on the disease, histology, and stage of the disease and on an assessment of individual patient tolerance.

• High-dose chemotherapy programs used in autologous and allogeneic hematopoietic cell transplantation result in additional organ toxicities that are not seen at conventional doses.

• Chemotherapy often targets process of DNA replication.

• More recently, drugs have been introduced to target specific cellular processes, including receptor signaling, inhibition of oncoproteins, angiogenesis, and membrane cluster of differentiation antigens.

COMBINATION CHEMOTHERAPY

• Combination chemotherapy uses several drugs simultaneously based on certain empiric principles:

  — Each drug selected has demonstrable antitumor activity against the neoplasm for which it is used.

  — Each drug should have a different mechanism of action.

  — The drugs should not have a common mechanism of resistance.

  — Drug dose-limiting toxicities should not overlap.

  — Specific combinations chosen should be based on preclinical and clinical protocol-based evidence of synergistic activity.

CELL KINETICS AND CANCER CHEMOTHERAPY

• Cell cycle–specific agents, such as antimetabolites, kill cells as they traverse the DNA synthetic phase (S phase) of the cell cycle.

  — Diminished killing of resting cells occurs.

  — Prolonged exposure to drug is useful for minimizing effects of asynchronous cell division.

  — High-dose regimens are the most useful.

• Non–cell cycle–dependent agents do not require cells to be exposed during a specific phase of the cell cycle.

  — Total dose of drug is more important than duration of exposure.

  — Appropriate dose depends on cell cycle dependence, toxicity to marrow and other tissues, pharmacokinetic behavior, interaction with other drugs, and patient tolerance.

DRUG RESISTANCE

• The basis for drug resistance is spontaneous occurrence of resistant cancer cell mutants and selection of drug-resistant cells under pressure of chemotherapy (clonal selection).

• Mechanisms such as additional mutations in mismatched repair genes and genes that block apoptosis also operate to impair treatment efficacy.

• Use of multiple drugs not sharing resistance mechanisms should be more effective than single agents.

• Multiple agents should be used simultaneously, because the probability of double- or triple-resistant cells is the product of the probabilities of the independent drug-resistant mutations occurring simultaneously in the same cell.

CELL CYCLE–SPECIFIC AGENTS

Methotrexate

• Methotrexate is used for maintenance therapy of acute lymphocytic leukemia, combination chemotherapy of lymphomas, and treatment and prophylaxis of meningeal leukemia.

• This agent inhibits dihydrofolate reductase, which leads to depletion of cellular folate coenzymes and to inhibition of DNA synthesis and cessation of cell replication.

• Acquired resistance is a result of increased levels of dihydrofolate reductase via gene amplification, defective polyglutamylation, and impaired cellular uptake.

• Doses ...