DNA topoisomerase II: a primer on the enzyme and its unique role as a multidrug target in cancer chemotherapy.
Based on the weight of evidence accrued in the past eight years, there is little question that the nuclear enzyme, topoisomerase II, serves as a common intracellular target for the cytotoxic effect of drugs of widely varying structure. The enzyme appears to be unique as a chemotherapy target in that it is recruited into a lethal process under the influence of drug. Its role contrasts sharply with other more classical chemotherapy targets, such as dihydrofolate reductase, whose activity must be successfully inhibited for the expression of cytotoxicity. Resistance to inhibitors of this enzyme frequently results from marked elevations in intracellular enzyme content. In contrast, the presence of topoisomerase is required for drug effect, and, in general, the greater the cellular content of the enzyme, the more sensitive the cell will be to these agents. However, important issues remain unresolved. The biochemical events that are initiated by cleavable complex formation and result in cell death must be more fully defined. It is likely a better understanding of the drug-enzyme interaction will be required for rational drug development. Finally, those aspects of the drug-topoisomerase interaction that confer therapeutic selectivity and/or clinical resistance are of paramount importance if the phenomenon is ever to be fully exploited.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000187:drug effects; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology*; D011034:Podophyllotoxin / Q000494:pharmacology* / Q000627:therapeutic use
D004273:DNA, Neoplasm; D007364:Intercalating Agents; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin