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Research ArticleArticle

Oxaliplatin-Induced Damage of Cellular DNA

Jan M. Woynarowski, Sandrine Faivre, Maryanne C.S. Herzig, Brenda Arnett, William G. Chapman, Alex V. Trevino, Eric Raymond, Stephen G. Chaney, Alexandra Vaisman, Maria Varchenko and Paul E. Juniewicz
Molecular Pharmacology November 2000, 58 (5) 920-927; DOI: https://doi.org/10.1124/mol.58.5.920
Jan M. Woynarowski
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Sandrine Faivre
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Maryanne C.S. Herzig
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Brenda Arnett
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William G. Chapman
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Alex V. Trevino
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Eric Raymond
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Stephen G. Chaney
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Alexandra Vaisman
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Maria Varchenko
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Paul E. Juniewicz
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Abstract

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.

Footnotes

    • Received February 17, 2000.
    • Accepted July 11, 2000.
  • Send reprint requests to: Jan M. Woynarowski, Ph.D., Cancer Therapy and Research Center, Institute for Drug Development, 14960 Omicron Dr., San Antonio, TX. E-mail: jmw1{at}saci.org

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

  • This study was supported in part by a grant from Sanofi-Synthelabo Research and by the National Institutes of Health Grant CA78706. E.R. was a recipient of fellowships from the Association pour la Recherche contre le Cancer (France) and from the Assistance Publique des Hôpitaux de Paris. A preliminary account of this study was presented in part at the 88th Annual Meeting of the American Association for Cancer Research, San Diego, CA, April 12 to 16, 1997, Proceedings, p 311, and the 90th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA, April 10 to 14, 1999, Proceedings, p 294.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 58 (5)
Molecular Pharmacology
Vol. 58, Issue 5
1 Nov 2000
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Research ArticleArticle

Oxaliplatin-Induced Damage of Cellular DNA

Jan M. Woynarowski, Sandrine Faivre, Maryanne C.S. Herzig, Brenda Arnett, William G. Chapman, Alex V. Trevino, Eric Raymond, Stephen G. Chaney, Alexandra Vaisman, Maria Varchenko and Paul E. Juniewicz
Molecular Pharmacology November 1, 2000, 58 (5) 920-927; DOI: https://doi.org/10.1124/mol.58.5.920

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Research ArticleArticle

Oxaliplatin-Induced Damage of Cellular DNA

Jan M. Woynarowski, Sandrine Faivre, Maryanne C.S. Herzig, Brenda Arnett, William G. Chapman, Alex V. Trevino, Eric Raymond, Stephen G. Chaney, Alexandra Vaisman, Maria Varchenko and Paul E. Juniewicz
Molecular Pharmacology November 1, 2000, 58 (5) 920-927; DOI: https://doi.org/10.1124/mol.58.5.920
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