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¹ Department of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands ² Laboratory of Molecular Genetics, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands ³ Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN ⁴ Faculty Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

Requests for Reprints: Jan H.M. Schellens, Division of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Phone: 31-20-5122569; Fax: 31-20-5122572. E-mail: jhm{at}nki.nl

Phase I and II clinical trails are currently investigating the antitumor activity of cisplatin and camptothecins (CPTs; DNA topoisomerase I poisons), based on the dramatic synergistic cytotoxicity of these agents in some preclinical models. However, the mechanistic basis for this synergism is poorly understood. By exploiting the evolutionary conservation of DNA repair pathways from genetically tractable organisms such as budding and fission yeasts to mammalian cells, we demonstrate that the synergism of CPT and cisplatin requires homologous recombination. In yeast and mammalian cell lines defective for RAD52 and XRCC2/3, respectively, the combination of these agents proved antagonistic, while greater than additive activity was evident in isogenic wild-type cells. Homologous recombination appears to mediate a similar interaction of X-rays and CPT, but antagonizes the synergism of cytarabine (Ara-C) with CPT. These findings suggest that homologous recombination comprises an evolutionarily conserved determinant of cellular sensitivity when CPTs are used in combination with other therapeutics.

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.

Note: Present address of R. van Waardenburg: Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN.

Received 5/23/03; revised 1/ 6/04; accepted 1/16/04.

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