International Commission for Protection Against Environmental Mutagens and Carcinogens. 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 complexes or from attempts by the cell to bypass the replication block caused by stabilized ternary complexes. Studies in bacterial mutation assays suggest that topoisomerase-interactive agents may also induce mutations, albeit at a lower rate, through simple DNA intercalation or via generation of oxygen free radicals. Second malignancies observed in patients previously treated with topoisomerase II interactive agents suggest these may be an important clinical consequence of their capacity to induce mutation. In particular, a unique form of acute myelogenous leukemia is observed at strikingly high frequencies after treatment with relatively high doses of the epipodophyllotoxins etoposide and teniposide. This form of AML has been reported after the uses of other classes of topoisomerase-interactive agents as well. Cancer induction is therefore a toxic consequence predicted by short-term tests of genotoxicity and should be weighed against the potential therapeutic benefits of topoisomerase-interactive agents.