BASIC PRINCIPLES OF CANCER CHEMOTHERAPY
Knowledge of drug actions, pharmacokinetics, clinical toxicities, and drug interactions is essential for the proper and safe administration of cancer chemotherapy.
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 stem cell transplantation result in additional organ toxicities that are not seen at conventional doses.
Chemotherapy usually 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 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.
— 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 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.
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, as 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.
DRUGS USED TO TREAT HEMATOLOGIC MALIGNANCIES
Methotrexate is used for maintenance therapy of acute lymphocytic leukemia, combination chemotherapy of lymphomas, and treatment and prophylaxis of meningeal leukemia.
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.
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