Damage to cellular DNA is believed to determine the antiproliferative properties of platinum (Pt) drugs. This study characterized DNA damage by oxaliplatin, a diaminocyclohexane Pt drug with clinical antitumor activity. Compared 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 microM drug/1 h, respectively, in CEM cells, P<.01). Oxaliplatin was found to induce potentially lethal bifunctional lesions, such as interstrand DNA cross-links (ISC) and DNA-protein cross-links (DPC) in CEM cells. As with total adducts, 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 microM drug, respectively, after a 4-h treatment. 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, observed in four cell lines, suggests that oxaliplatin adducts are repaired with similar kinetics as cisplatin adducts. Oxaliplatin, however, was more efficient than cisplatin per equal number of DNA adducts in inhibiting DNA chain elongation ( approximately 7-fold in CEM cells). Despite lower DNA reactivity, oxaliplatin exhibited similar or greater cytotoxicity in several other human tumor cell lines (50% growth inhibition in CEM cells at 1.1/1.2 microM, respectively). The results demonstrate that oxaliplatin-induced DNA lesions, including ISC and DPC, are likely to contribute to the drug's biological properties. However, oxaliplatin requires fewer DNA lesions than does cisplatin to achieve cell growth inhibition.

Oxaliplatin is a clinical anticancer drug with a pharmacological profile distinct from that of cisplatin. Our studies compared site- and region-specificity of lesions induced by oxaliplatin and cisplatin in naked and intracellular DNA, respectively. Oxaliplatin adducts in naked Simian virus 40 (SV40 DNA) were mapped by repetitive primer extension. The sites of oxaliplatin adducts were nearly identical to the sites of cisplatin adducts and were focused in G clusters and GNG motifs probably reflecting intrastrand cross-links. Although alkaline agarose electrophoresis of specific SV40 fragments showed that oxaliplatin formed interstrand cross-links, the levels of this lesion type were low. Drug-induced lesions in discrete loci of cellular DNA were assessed by the polymerase chain reaction stop assay in human tumor A2780 cells. Oxaliplatin at 200 microM induced approximately 1300, approximately 1500, approximately 800, and approximately 300 lesions/10(6) bp in the human beta-globin, c-myc, and HPRT genes and in mitochondrial DNA, respectively. Cisplatin formed two to six times more lesions in the same regions. For both drugs, lesion frequencies seem to parallel the density of drug-binding motifs in the nuclear regions, whereas mitochondrial DNA was disproportionately less affected. Despite less potent induction of DNA lesions, oxaliplatin was more cytotoxic than cisplatin against A2780 cells. Because our findings clearly demonstrate that oxaliplatin forms covalent adducts with a similar sequence- and region-specificity to that of cisplatin, other properties of oxaliplatin adducts, factors other than DNA binding, or both determine the unique features of the mechanism of action of oxaliplatin.

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A survey for bacteriuria was conducted in a community-wide, unselected population of women 16--69 years old. The overall prevalence of bacteriuria was 3.5%. The prevalence of bacteriuria increased with age with a linear trend, but with a significant nonlinear component as well. Bacteriuria was associated with parity after correction for the effects of age. Current symptoms of dysuria and a history of previous urinary tract infection were slightly but significantly more common in women with bacteriuria. The population described should serve as an adequate base for continuing studies of the possible consequences of bacteriuria.