Preliminary evaluation of treatment and selection conditions which affect expression of anthracycline mutagenicity in Salmonella typhimurium and a diploid human lymphoblast cell line.

Abstract

Mutagenic potency in the Ames Salmonella test is an important endpoint that can be influenced by biological and technical factors. The ranking of mutagenic activity of a series of anthracyclines was measured using different conditions of exposure and mutation selection. A 20 min preincubation treatment version of the Ames test using a 0.2-2.0 microgram/ml (0.36-3.60 nM/ml) dose range of each of the anthracyclines Adriamycin, Daunomycin, Carminomycin, 4'-O-methyldoxorubicin and 4-demethoxydoxorubicin confirmed the order of mutagenic potency seen with the same compounds under direct plating conditions. Preincubation results also confirm direct-plating results by showing the greater sensitivity of selection to His+ reversion over 8-azaguanine resistance to anthracycline mutagenicity. However, the order of mutagenic potency was changed by lengthening the preincubation treatment time to 2 h or reducing the population density of the treated cell inoculum by ten fold. These results suggest that certain treatment conditions enable the treated cells to diminish the phenotypic expression of anthracycline mutagenicity. For comparative purposes, daunomycin and Adriamycin mutagenicity in response to 0.1-0.2 nM/ml and 0.1-0.3 nM/ml dose ranges, respectively, were assessed in a human cell culture system with 6-thioguanine and 5-trifluorothymidine forward mutation selection. A daunomycin dose of 0.1 nM/ml generated approximately 25-fold and 20-fold increases in mutant fraction with 6-thioguanine and 5-trifluorothymidine selections, respectively. Equivalent dosing with Adriamycin generated approximately a 4-fold increase in mutant fraction with 6-thioguanine selection and little or no increase with 5-trifluothymidine selection.(ABSTRACT TRUNCATED AT 250 WORDS)