Comparative analysis of the mutagenic activity of oxaliplatin and cisplatin in the Hprt gene of CHO cells

Abstract

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.

Platinum–DNA Interactions and Subsequent Cellular Processes Controlling Sensitivity to Anticancer Platinum Complexes

“…Mismatch repair (MMR) is a post-replication repair system that corrects mispaired and unpaired bases in the duplex [75]. MMR System repairs mismatches caused by adducts that are not removed by the NER system [12]. The DNA-mismatch repair system, e.g., Msh2 corrects base -base mismatches and small loops, whereas the NER system, e.g., Rad1, removes pyrimidine dimers and other helix-distorting lesions [123].…”

“…The lower levels of Pt-adduct formation with oxaliplatin most likely reflect the slow dissociation rate of the oxalate ligand under physiological conditions. It has been suggested that oxaliplatin cytotoxicity might possibly result from proportionately more highly lethal lesions such as interstrand or DNA -protein cross-links [70], and from the bulkier and more hydrophobic adducts formed by oxaliplatin [12]. Recent investigations suggest that oxaliplatin displays a disproportionately greater ability to induce secondary lesions in DNA that are precursors to massive apoptosis [72].…”

“…Carboplatin has approximately the same spectrum of activity as cisplatin but reduced toxicity [9 -11]. Oxaliplatin is particularly effective in the treatment of primary advanced colorectal cancer and cisplatin-resistant ovarian cancers [12] [13].…”

Increased levels and defective glycosylation of MRPs in ovarian carcinoma cells resistant to oxaliplatin

“…Although the low spontaneous mutation frequency is unlikely to generate mutations in the potential N-glycosylation sites in MRP4, oxaliplatin is quite mutagenic to mammalian cells [31] and such mutations may have arisen during the selection process. To determine whether mutation of the N-glycosylation sites in MRP4 could account for the observed glycosylation defect, we sequenced the putative glycosylation sites with primers designed using web available tools.…”

DNA Polymerase Eta and Chemotherapeutic Agents

“…Both cisplatin and carboplatin are effective against solid tumors such as small-cell lung, ovarian, head, and neck cancers. Oxaliplatin is often used for the treatment of primary advanced colorectal cancer and cisplatinresistant ovarian cancers (57,66). Although cisplatin and its analogs are widely used clinically, a major limitation for these compounds is the induced drug resistance.…”