MUTAGENICITY AND CARCINOGENICITY OF TOPOISOMERASE-INTERACTIVE AGENTS

Drugs that interact with DNA topoisomerases I and II hold great promise for the treatment of cancer, however, like many other anti-cancer agents, they are a double-edged sword and may themselves cause mutation and cancer. In vitro studies show that clinically effective agents, such as etoposide, doxorubicin and others, stabilize a ternary complex where topoisomerase II is covalently linked to DNA. This complex represents an intermediate in the topoisomerase-II catalyzed DNA supercoil relaxation reaction. Camptothecin and its analogues stabilize a similar ternary complex, in vitro, consisting of topoisomerase I covalently linked to DNA at single-strand breaks. Short-term tests of genotoxicity confirm that topoisomerase-interactive agents are mutagenic and suggest common mechanisms by which they induce mutation and selectively kill tumor cells. These agents induce sister-chromatid exchange, chromosomal aberrations and mutations in specific mammalian genes. Their propensity to induce small colonies in the L5178/TK+/--3.7.2C assay implies that topoisomerase-interactive agents induce large DNA rearrangements and deletions. These may result from topoisomerase-subunit exchange at drug-stabilized ternary