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

Abstract

We evaluated the ability of the antitumor agent 4-(9-acridinylamino)-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 approximately 3000 mutants/10(6) survivors at 10% survival; positive dose range 1-10 ng/ml; o-AMSA produced approximately 1500 mutants/10(6) survivors at 10% survival; positive dose range 0.1-2.5 micrograms/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 microgram/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 - 112/10(6) survivors; background = 7/10(6); survival = 63 - 16%) were comparable to the published HPRT mutant frequencies produced by m-AMSA in V79 cells. Novobiocin (50 micrograms/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/clastogenic activity of m-AMSA.

• Authors: D M DeMarini, C L Doerr, M K Meyer, K H Brock, J Hozier, M M Moore
• Journal: Mutagenesis (Mutagenesis) Vol. 2 Issue 5 Pg. 349-55 (Sep 1987) ISSN: 0267-8357 [Print] England
• PMID: 2830452 (Publication Type: Journal Article)

Chemical References

• Mutagens
• Amsacrine
• 4'-(9-acridinylamino)methanesulfon-o-anisidide
• Hypoxanthine Phosphoribosyltransferase
• Thymidine Kinase
• DNA Topoisomerases, Type II

Topics

• Amsacrine (analogs & derivatives, toxicity)
• Animals
• Cell Survival (drug effects)
• Chromosome Aberrations
• DNA Topoisomerases, Type II (metabolism)
• Hypoxanthine Phosphoribosyltransferase (genetics)
• Isomerism
• Leukemia L5178 (enzymology)
• Mice
• Mutagens
• Mutation
• Thymidine Kinase (genetics)