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Mutagenesis vol. 2 no. 5 pp. 349-355, 1987
© 1987 UK Environmental Mutagen Society/Oxford University Press

other

Mutagenicity of m-AMSA and o-AMSA in mammalian cells due to clastogenic mechanism: possible role of topoisomerase

David M. DeMarini1,2, Carolyn L. Doerr3, Mary K. Meyer3, Karen H. Brock3, John Hozier4 and Martha M. Moore1

1Genetic Toxicology Division, Health Effects Research Laboratory, US Environmental Protection Agency Research Triangle Park, NC 27711 3Environmental Health Research and Testing PO Box 12199, Research Triangle Park, NC 27709 4Department of Biological Science, Florida State University Tallahassee, FL 32306, USA

We evaluated the ability of the antitumor agent 4-(9-acridinyl-amino)-methanesulfon-m-anisidide (amsacrine or m-AMSA) and its congener, o-AMSA, to induce specific-locus mutations at the heterozygous thymidine kinase (tk) locus of L5178Y/TK+/–-3.7.2C mouse lymphoma cells. These cells permit the recovery of mutants due to single-gene or chromosomal mutation. m-AMSA was highly mutagenic at the tk locus, producing {small tilde}3000 mutants/106 survivors at 10% survival; positive dose range 1–10 ng/ml; o-AMSA produced {small tilde}1500 mutants/106 survivors at 10% survival; positive dose range 0.1–2.5 µg/ml. Most of the TK mutants were small colonies, which suggests that m-AMSA and o-AMSA induce primarily chromosomal mutations as opposed to single-gene mutations. The potent clastogenicity of these agents was confirmed by cytogenetic analysis for chromosomal aberrations, which showed that m-AMSA (9 ng/ml, 10% survival) and o-AMSA (1 µg/ml, 10% survival) produced 383 and 179 aberrations, respectively, per 100 metaphases (background = 3–4/100). The large-colony TK mutant frequencies produced by m-AMSA (67–112/106 survivors; background = 7/106; survival = 63–16%) were comparable to the published HPRT mutant frequencies produced by m-AMSA in V79 cells. Novobiocin (50 µg/ml), an inhibitor of mammalian DNA topoisomerase II and other enzymes, inhibited the mutagenic effects of m-AMSA, suggesting that DNA topoisomerase II (or another enzyme) may play a role in the mutagenic/clasto-genic activity of m-AMSA.

2To whom reprint should be addressed


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K. Patteson, P. Wang, and L. F. Povirk
Enhanced Amsacrine-induced Mutagenesis in Plateau-Phase Chinese Hamster Ovary Cells, with Targeting of +1 Frameshifts to Free 3' Ends of Topoisomerase II Cleavable Complexes
Cancer Res., August 1, 1999; 59(15): 3682 - 3688.
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