Mutagenicity of topoisomerase-active agents in bacteriophage T4.
Recently, the antitumor agent 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) was shown to revert a frameshift mutant of T4 (rFC11), and its mutagenicity was shown to be mediated by T4 DNA topoisomerase II [Ripley et al.: J Mol Biol 200: 665-680, 1988]. Here we report dose-response data on the mutagenicity and toxicity of m-AMSA in T4 rFC11. We find that m-AMSA is among the most potent frameshift mutagens observed in T4, inducing a 10-fold increase in mutant frequency in the absence of toxicity and a 500-fold increase in mutant frequency at 31% survival. In addition to m-AMSA, the topoisomerase-active agents ellipticine, oxolinic acid, and nalidixic acid also reverted rFC11; however, they required concentrations 10-100 times greater than those required by m-AMSA in order to be mutagenic, and they did not produce mutant frequencies as high as those produced by m-AMSA. Unlike m-AMSA, all three agents were mutagenic only at toxic doses. The other agents evaluated--actinomycin D, adriamycin, 9-aminoellipticine, 9-methoxyellipticine, teniposide (VM-26), and novobiocin--were toxic but not mutagenic to T4 rFC11. Thus, m-AMSA appears to be distinctly different from the other topoisomerase-active agents in exhibiting such potent mutagenic activity in T4 rFC11. Because E. coli DNA gyrase may substitute for T4 topoisomerase II, we examined the ability of two inhibitors of E. coli DNA gyrase, novobiocin and nalidixic acid, to inhibit m-AMSA's mutagenicity. Both agents substantially reduced the mutagenicity of m-AMSA in T4 rFC11, further suggesting that topoisomerase mediates the mutagenicity of m-AMSA.
DeMarini
D M
DM
Genetic Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
Lawrence
B K
BK
D000677:Amsacrine / Q000633:toxicity*; D004250:DNA Topoisomerases, Type II; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004611:Ellipticines / Q000494:pharmacology; D009154:Mutation; D009268:Nalidixic Acid / Q000494:pharmacology; D009675:Novobiocin / Q000494:pharmacology; D010093:Oxolinic Acid / Q000494:pharmacology; D013604:T-Phages / Q000187:drug effects*
D004611:Ellipticines; D000677:Amsacrine; D009675:Novobiocin; D003609:Dactinomycin; D009268:Nalidixic Acid; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; D010093:Oxolinic Acid