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Originally published In Press as doi:10.1074/jbc.M104383200 on September 27, 2001

J. Biol. Chem., Vol. 276, Issue 48, 44488-44494, November 30, 2001
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Topoisomerase II Poisoning by ICRF-193*

Kuan-Chun HuangDagger §, Hanlin GaoDagger §, Edith F. YamasakiDagger , Dale R. Grabowski||, Shujun LiuDagger , Linus L. Shen**, Kenneth K. ChanDagger Dagger , Ram Ganapathi||, and Robert M. SnapkaDagger §§§

From the Departments of Dagger  Radiology and § Molecular Virology, Immunology, and Medical Genetics, The Ohio State University College of Medicine, Columbus Ohio, 43210, the || Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195, the Dagger Dagger  College of Medicine and College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, and ** Abbott Laboratories, Abbott Park, Illinois 60064

Antineoplastic bis(dioxopiperazine)s, such as meso-2,3-bis(2,6-dioxopiperazin-4-yl)butane (ICRF-193), are widely believed to be only catalytic inhibitors of topoisomerase II. However, topoisomerase inhibitors have little or no antineoplastic activity unless they are topoisomerase poisons, a special subclass of topoisomerase-targeting drugs that stabilize topoisomerase-DNA strand passing intermediates and thus cause the topoisomerase to become a cytotoxic DNA-damaging agent. Here we report that ICRF-193 is a very significant topoisomerase II poison. Detection of topoisomerase II poisoning by ICRF-193 required the use of a chaotropic protein denaturant in the topoisomerase poisoning assays. ICRF-193 caused dose-dependent cross-linking of human topoisomerase IIbeta to DNA and stimulated topoisomerase IIbeta -mediated DNA cleavage at specific sites on 32P-end-labeled DNA. Human topoisomerase IIalpha -mediated DNA cleavage was stimulated to a lesser extent by ICRF-193. In vivo experiments with MCF-7 cells also showed the requirement of a chaotropic protein denaturant in the assays and selectivity for the beta -isozyme of human topoisomerase II. Studies with two topoisomerase IIbeta -negative cell model systems confirmed significant topoisomerase II poisoning by ICRF-193 in the wild type cells and were consistent with beta -isozyme selectivity. Common use of only the detergent, SDS, in assays may have led to failure to detect topoisomerase II poisoning by ICRF-193 in earlier studies.

* This work was supported by Grant NCI RO1 CA80961 (to R. M. S.), Contract NO1-CM-57201 (to K. K. C.), Grant U01CA63185 (to K. K. C. and R. M. S.), Grants DK56917 and CA74939 (to R. G.), and Grant P30 CA16058 (to the Ohio State University Comprehensive Cancer Center) from the Public Health Service.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

§§ To whom correspondence should be addressed: Ohio State University, Dept. of Radiology, 103 Wiseman Hall, 400 West 12th Ave., Columbus, OH 43210. Tel.: 614-292-9375; Fax: 614-292-7237; E-mail: snapka.1@osu.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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