Comparison of the mutagenic responses of 12 anticancer drugs at the hypoxanthine‐guanine phosphoribosyl transferase and adenosine kinase loci in chinese hamster ovary cells

Abstract

5he mutagenic responses of 12 anticancer drugs--lomustine, dacarbazine, mitomycin C, chlorambucil, cis-diamminedichloroplatinum (II), busulfan, ellipticine, daunomycin, adriamycin, VM-26, VP16-213, and bleomycin--in Chinese hamster ovary (CHO) cells at two independent genetic loci which affect purine salvage pathway enzymes, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and adenosine kinase (AK) have been compared within the same experiments. The cellular mutants which lack either HGPRT (HGPRT- mutants) or AK (AK- mutants) activity can be directly selected in CHO cells using 6-thioguanine and 6-methyl mercaptopurineriboside (6-MeMPR) respectively, and optimal conditions for their selection have been described. Results of our studies show that all of the above drugs caused a concentration-dependent increase in the frequencies of both 6-thioguanine- and 6-MeMPR-resistant mutants. However, for a number of these drugs, namely adriamycin, daunomycin, bleomycin, and dacarbazine, which are only weakly mutagenic at the HGPRT locus, a relatively strong and clear mutagenic response was observed at the AK locus. In contrast, VM-26 showed a more pronounced effect at the HGPRT locus. For the remaining compounds, the mutagenic responses of the two loci (as indicated by the slopes of the dose-response curves) were comparable. The observed increase in the frequency of AK- mutants after treatment with various drugs, many of which predominantly induce frameshift and chromosome-breakage type of genetic lesions, suggests that like the HGPRT locus the AK locus is also capable of detecting all the different types of genetic lesions. The favorable response of the AK locus as compared to that of HGPRT locus in these studies indicates that the selection system of AK- mutants should provide a very useful genetic marker for mutagenesis studies in CHO cells.