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¹ Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, California; ² Division of Hematology/Medical Oncology, Vanderbilt University Medical Center, Nashville, Tennessee; ³ Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; and ⁴ University of Pittsburgh, Pittsburgh, Pennsylvania

Requests for Reprints: Allan Y. Chen, Department of Radiation Oncology, University of California Davis Medical Center, 4501 "X" Street, G-126, Sacramento, CA 95817. Phone: 916-734-8252; Fax: 916-454-4614. E-mail: aychen{at}ucdavis.edu

The silatecan 7-tert-butyldimethylsilyl-10-hydroxy-camptothecin (DB-67) represents a new generation of camptothecin derivatives that exhibits a potent in vitro DNA topoisomerase I (TOP1)–mediated DNA-damaging activity, improved blood stability, and holds significant promise for the treatment of human cancers. In this study, we characterize the role of TOP1 in mediating the radiosensitization activity of DB-67. As examined by clonogenic survival assay, DB-67 exhibited potent radiosensitization activity at a concentration 10-fold lower than camptothecin in the human glioma D54-MG and T-98G cells, which harbor wild-type and mutant p53, respectively. Analyzed by the single-hit multitarget model, DB-67 induced radiosensitization by obliterating the "shoulder" of the radiation survival curve in the D54-MG cells. The in vivo targeting of TOP1 by DB-67 was investigated by immunoblot analysis. In a dose-dependent manner, DB-67 specifically stimulates covalent linking of TOP1 to chromosomal DNA at concentrations 10-fold lower than camptothecin in the D54-MG cells. The potency of in vivo targeting of TOP1 by DB-67 correlates well with its cytotoxicity and radiosensitization activity. Furthermore, DB-67 exhibited substantially less cytotoxicity and radiosensitization activity in the TOP1 mutant Chinese hamster lung fibroblast DC3F/C-10 cells than in their parental DC3F cells. Together, our data show that DB-67 exhibits potent cytotoxicity and radiosensitization activity by targeting TOP1 in mammalian cells and has great potential for being developed to treat human cancers.

Key Words: radiosensitization • silatecan DB-67 • DNA topoisomerase I • camptothecin • glioma

Grant support: American Cancer Society Institutional Research Grant no. IRG-95-125-07 and University of California Davis Health System Award (A.Y. Chen).

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: Presented in part at the AACR Annual Meeting, April 2001, New Orleans, Louisiana.

⁵ A.Y. Chen, unpublished results.

Received 9/20/04; revised 11/22/04; accepted 11/30/04.