Comparison of the mutagenic and clastogenic activity of amsacrine and other DNA-intercalating drugs in cultured V79 Chinese hamster cells

Abstract

The acridine derivative amsacrine (m-AMSA) is used clinically for the treatment of acute leukemias. The mutagenic activity of this drug has been evaluated at the 6-thioguanine (6-TG) and ouabain resistance loci in cultured Chinese hamster fibroblasts (V79-171b cell line). m-AMSA was found to have weak but significant mutagenic activity at the 6-TG but not at the ouabain resistance locus, after either 1- or 45-hr exposures at concentrations causing up to 90% cell kill. Two other intercalating agents with antitumor activity, Adriamycin and actinomycin D, provided essentially identical results. All three drugs were potent inducers of micronuclei in V79-171b cells, indicating high clastogenic activity. For these intercalating agents, the yield of 6-TG-resistant mutants was approximately 100-fold lower than that for ethyl methanesulfonate after exposures causing equivalent toxicity or equivalent chromosome breakage. The acridine half-mustard ICR-191 resembled ethyl methanesulfonate rather than the other intercalating agents in providing a high yield of 6-TG-resistant mutants relative to its clastogenic activity. The tumor-inactive intercalator 9-aminoacridine demonstrated only low clastogenic activity with a lack of significant mutagenic activity at toxic concentrations. These results suggest that, for m-AMSA, Adriamycin, and actinomycin D, both cell killing and mutagenesis could be direct consequences of chromosome breakage, while 9-aminoacridine may kill cells by a different mechanism. In view of its mutagenic and clastogenic activity at clinically achievable exposures and the similarity of its genotoxic properties to Adriamycin, m-AMSA should be considered a potential carcinogen.