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J. Biol. Chem., Vol. 280, Issue 14, 14349-14355, April 8, 2005

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The Role of Checkpoint Kinase 1 in Sensitivity to Topoisomerase I Poisons^*

Karen Flatten, Nga T. Dai, Benjamin T. Vroman, David Loegering, Charles Erlichman, Larry M. Karnitz¶||**, and Scott H. Kaufmann¶||

From the Divisions of Oncology Research and Medical Oncology, Mayo Clinic and ^¶Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Agents that target topoisomerase I are widely utilized to treat human cancer. Previous studies have indicated that both the ataxia telangiectasia mutated (ATM)/checkpoint kinase (Chk) 2 and ATM- and Rad 3-related (ATR)/Chk1 checkpoint pathways are activated after treatment with these agents. The relative contributions of these two pathways to survival of cells after treatment with topoisomerase I poisons are currently unknown. To address this issue, we assessed the roles of ATR, Chk1, ATM, and Chk2 in cells treated with the topoisomerase I poisons camptothecin and 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Colony forming assays demonstrated that down-regulation of ATR or Chk1 sensitized cells to SN-38 and camptothecin. In contrast, ATM and Chk2 had minimal effect of sensitivity to SN-38 or camptothecin. Additional experiments demonstrated that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin, which down-regulates Chk1, also sensitized a variety of human carcinoma cell lines to SN-38. Collectively, these results show that the ATR/Chk1 pathway plays a predominant role in the response to topoisomerase I inhibitors in carcinoma cells and identify a potential approach for enhancing the efficacy of these drugs.

Received for publication, October 19, 2004 , and in revised form, January 4, 2005.

^* This work was supported in part by National Institutes of Health Grants CA73709 (to S. H. K.), CA104378 (to L. M. K.), and CA90390 (to C. E.). 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.

^|| Both authors contributed equally to this work.

^** To whom correspondence may be addressed: Div. of Oncology Research, Guggenheim 1301, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905. Phone: 507-284-3124; Fax: 507-284-3906; E-mail: Karnitz.Larry{at}Mayo.edu. To whom may be addressed: Div. of Oncology Research, Guggenheim 1301, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905. Tel.: 507-284-8950; Fax: 507-284-3906; E-mail: Kaufmann.Scott{at}Mayo.edu.

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