ADRIAMYCIN INDUCES LARGE DELETIONS AS A MAJOR TYPE OF MUTATION IN CHOCELLS

Adriamycin (ADR), a commonly used cancer chemotherapy antibiotic, exhi bits a variety of genotoxicities. In this study, we have examined the mutagenicity of ADR at the hypoxanthine-guanine phosphoribosyltransfer ase gene (hprt) in Chinese hamster ovary (CHO) cells and the xanthine- guanine phosphoribosyltransferase locus (gpt) in a pSV2gpt-transformed CHO cell line, AS52. Although ADR induced a dose-dependent increase o f mutant frequency at both loci, it was more mutagenic to the gpt gene than to the hprt locus. Multiplex PCR analysis revealed that 35% of t he 103 independent ADR-induced HPRT-deficient mutants carried large de letions. Among these deletion mutants, 33% were total gene deletions, 22% affected multiple exons, and 42% involved a single exon, of which most (9/15) were exon 1. The majority (63%) of ADR-induced AS52 mutant s had a total deletion of the gpt gene. These observations indicate th at ADR induces large deletions as a major type of gene mutation in mam malian cells, suggesting the involvement of reactive oxygen species as one mutagenic pathway in the mutagenesis of ADR.