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Vol. 58, Issue 5, 920-927, November 2000

Oxaliplatin-Induced Damage of Cellular DNA

Jan M. Woynarowski, Sandrine Faivre,1 Maryanne C.S. Herzig, Brenda Arnett, William G. Chapman, Alex V. Trevino, Eric Raymond,1 Stephen G. Chaney, Alexandra Vaisman, Maria Varchenko, and Paul E. Juniewicz

Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, Texas (J.M.W., S.F., M.C.S.H., B.A., W.G.C., E.R., A.V.T.); Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (A.V., M.V., S.G.C.); and Sanofi-Synthelabo Research, Malvern, Pennsylvania (P.E.J.)

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/106 base pairs/10 µM 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/106 base pairs/10 µM 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 (~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 µM, 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.

1 Present address: Departement de Medecine, Institut Gustave-Roussy, 39, rue Camille-Desmoulins 94800 Villejuif, France.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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