Alkylating agents and platinum: is clinical resistance simply a tumor cell phenomenon?
Alkylating agents and platinum compounds comprise a large group of drugs that may exhibit marked differences in pharmacologic properties on the subcellular and clinical levels. Studies of the subcellular pharmacology of individual agents in this group suggest that cellular resistance to these drugs as a class may be modulated at three general levels: transmembrane drug accumulation, cytosolic inactivation of drug, and altered DNA repair. Traditionally, one unspoken assumption of cancer chemotherapy has been that in vitro tumor cell resistance equates with clinical resistance. Recent studies of platinum DNA adduct in nonmalignant tissues from cancer patients actively receiving therapy suggest that this assumption should be reassessed. In studies of platinum-DNA adduct from four different groups (using four different methods to assess adduct levels in nonmalignant tissues), the relationship between adduct level and disease response is a direct one; ie, the higher the adduct level, the better the clinical response to therapy. Here the data are reviewed that suggest that clinical resistance to DNA-damaging agents is not simply a tumor cell phenomenon and may represent the pharmacogenetic ability of individuals to protect cellular DNA.
Reed
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Section of Genitourinary Cancer, National Cancer Institute, Bethesda, MD 20892.
D000477:Alkylating Agents / Q000494:pharmacology*; D004249:DNA Damage / Q000235:genetics; D004351:Drug Resistance / Q000502:physiology; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D009369:Neoplasms / Q000235:genetics*; D010984:Platinum / Q000494:pharmacology*
D000477:Alkylating Agents; D010984:Platinum