Oxaliplatin is a platinum-derived antitumor drug that is active against cisplatin-resistant tumors and has lower overall toxicity than does cisplatin. DNA adduct formation is believed to mediate the cytotoxic activity of both compounds; however, the adducts may also be responsible for mutagenic and secondary tumorigenic activities. In this study, we have compared the mutagenicity of oxaliplatin and cisplatin in the Hprt gene of CHO-K1 cells. Both drugs produced dose-related increases in mutant frequency. For 1-hr treatments, oxaliplatin was less mutagenic than cisplatin at equimolar doses, while similar mutant frequencies were induced at equitoxic doses. Sequencing of mutant Hprt genes indicated that the mutation spectra of both oxaliplatin and cisplatin were significantly different from the spontaneous mutation spectrum (P = 0.014 and P = 0.008, respectively). A significant difference was also observed between the spectra of oxaliplatin- and cisplatin-induced mutations (P = 0.033). Although G:C-->T:A transversion was the most common mutation produced by both compounds, oxaliplatin produced higher frequencies of A:T-->T:A transversion than did cisplatin, most commonly at nucleotide 307, and higher frequencies of small deletions/insertions. Also, cisplatin induced tandem base-pair substitutions, mainly at positions 135/136, and a higher frequency of G:C-->A:T transition than did oxaliplatin. These results provide the first evidence that oxaliplatin is mutagenic and that the profiles of cisplatin- and oxaliplatin-induced mutations display not only similarities but also distinctive features relating to the type and sequence-context preference for mutation. Environ.
Copyright 2005 Wiley-Liss, Inc.