Oxaliplatin-induced damage of cellular DNA

Damage to cellular DNA is believed to determine the antiproliferative prope rties of platinum (Pt) drugs. This study characterized DNA damage by oxalip latin, a diaminocyclohexane Pt drug with clinical antitumor activity. Compa red with cisplatin, oxaliplatin formed significantly fewer Pt-DNA adducts ( e.g., 0.86 +/- 0.04 versus 1.36 +/- 0.01 adducts/10(6) base pairs/10 mu M d rug/1 h, respectively, in CEM cells, P < .01). Oxaliplatin was found to ind uce potentially lethal bifunctional lesions, such as interstrand DNA cross- links (ISC) and DNA-protein cross-links (DPC) in CEM cells. As with total a dducts, however, oxaliplatin produced fewer (P < .05) bifunctional lesions than did cisplatin: 0.7 +/- 0.2 and 1.8 +/- 0.3 ISC and 0.8 +/- 0.1 and 1.5 +/- 0.3 DPC/10(6) base pairs/10 mu M drug, respectively, after a 4-h treat ment. Extended postincubation (up to 12 h) did not compensate the lower DPC and ISC levels by oxaliplatin. ISC and DPC determinations in isolated CEM nuclei unequivocally verified that oxaliplatin is inherently less able than cisplatin to form these lesions. Reactivation of drug-treated plasmids, ob served in four cell lines, suggests that oxaliplatin adducts are repaired w ith similar kinetics as cisplatin adducts. Oxaliplatin, however, was more e fficient than cisplatin per equal number of DNA adducts in inhibiting DNA c hain elongation (similar to 7 fold in CEM cells). Despite lower DNA reactiv ity, oxaliplatin exhibited similar or greater cytotoxicity in several other human tumor cell lines (50% growth inhibition in CEM cells at 1.1/1.2 mu M , respectively). The results demonstrate that oxaliplatin-induced DNA lesio ns, including ISC and DPC, are likely to contribute to the drug's biologica l properties. However, oxaliplatin requires fewer DNA lesions than does cis platin to achieve cell growth inhibition.