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J. Biol. Chem., Vol. 279, Issue 52, 54502-54509, December 24, 2004

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Platinated DNA Adducts Enhance Poisoning of DNA Topoisomerase I by Camptothecin^*

Robert C. A. M. van Waardenburg, Laurina A. de Jong, Maria A. J. van Eijndhoven, Caroline Verseyden, Dick Pluim, Lars E. T. Jansen¶, Mary-Ann Bjornsti||, and Jan H. M. Schellens, Supported by Dutch Cancer Society K. W. F. Grant NKI 97-1440**

From the Department of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands, the Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, the ^¶MGC Department of Molecular Genetics, Leiden Institute of Chemistry, Leiden University, 2300 RA Leiden, The Netherlands, and the ^**Faculty of Pharmaceutical Sciences, University Utrecht, P.O. Box 80082, 3508TB Utrecht, The Netherlands

Camptothecins constitute a novel class of chemotherapeutics that selectively target DNA topoisomerase I (Top1) by reversibly stabilizing a covalent enzyme-DNA intermediate. This cytotoxic mechanism contrasts with that of platinum drugs, such as cisplatin, which induce inter- and intrastrand DNA adducts. In vitro combination studies using platinum drugs combined with Top1 poisons, such as topotecan, showed a schedule-dependent synergistic activity, with promising results in the clinic. However, whereas the molecular mechanism of these single agents may be relatively well understood, the mode of action of these chemotherapeutic agents in combination necessitates a more complete understanding. Indeed, we recently reported that a functional homologous recombination pathway is required for cisplatin and topotecan synergy yet represses the synergistic toxicity of 1--D-arabinofuranosyl cytidine in combination with topotecan (van Waardenburg, R. C., de Jong, L. A., van Delft, F., van Eijndhoven, M. A., Bohlander, M., Bjornsti, M. A., Brouwer, J., and Schellens, J. H. (2004) Mol. Cancer Ther. 3, 393–402). Here we provide direct evidence for Pt-1,3-d(GTG) poisoning of Top1 in vitro and demonstrate that persistent Pt-DNA adducts correlate with increased covalent Top1-DNA complexes in vivo. This contrasts with a lack of persistent lesions induced by the alkylating agent bis[chloroethyl]nitrosourea, which exhibits only additive activity with topotecan in a range of cell lines. In human IGROV-1 ovarian cancer cells, the synergistic activity of cisplatin with topotecan requires processive DNA polymerization, whereas overexpression of Top1 enhances yeast cell sensitivity to cisplatin. These results indicate that the cytotoxic activity of cisplatin is due, in part, to poisoning of Top1, which is exacerbated in the presence of topotecan.

Received for publication, September 2, 2004 , and in revised form, September 24, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Supported by National Institutes of Health Grants CA58755, CA23099, and CA21765 and American Lebanese Syrian Associated Charities.

To whom correspondence should be addressed: Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel.: 31-20-5122446; Fax: 31-20-5122572; E-mail: jhm{at}nki.nl.

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