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Radiation Oncology Branch [A. Y. C., P. O.], Laboratory of Molecular Pharmacology [Y. P.], and Radiation Biology Branch [J. B. M.], National Cancer Institute, NIH, Bethesda, Maryland 20892
The role of DNA topoisomerase I as a biochemical mediator of radio-sensitization in cultured mammalian cells by camptothecin derivatives was studied. We found that, in Chinese hamster DC3F cells, camptothecin enhanced the cytotoxicity of radiation in a schedule-dependent manner. At 4 µM, a sensitizer enhancement ratio of 1.45 was observed when radiation was used concurrently with or immediately after drug treatment. By comparison, no enhancement was obtained if radiation preceded camptothecin treatment. Consistently, in human breast cancer MCF-7 cells, sensitizer enhancement ratios of 1.43, 1.38, and 1.05 were observed when radiation was used concurrently with, immediately after, or prior to treatment with 20(S)-10,11-methylenedioxycamptothecin (MDCamp).
Three studies indicated that an intact stereospecific interaction between camptothecin derivatives and DNA topoisomerase I is essential in the induction of radiosensitization: (a) higher concentrations of camptothecin were required to radiosensitize the camptothecin-resistant DC3F/C-10 cells; (b) a newly identified topoisomerase I-targeting Hoechst 33342 also radiosensitized DC3F cells; and (c) 20(S)-methylenedioxycamptothecin, but not its noncytotoxic 20(R)-stereoisomer, radiosensitized MCF-7 cells by obliterating the "shoulder" of the radiation survival curve.
The mechanism of radiosensitization was investigated in DC3F cells. We found that camptothecin only minimally enhanced the cytoxic effect of radiation in G1-phase cells obtained by a mitotic shake-off technique as well as in plateau-phase cells arrested by growing to confluency.
Our data suggest a potential development of topoisomerase I drugs as radiosensitizers in treating human malignancies.
1 To whom requests for reprints should be addressed, at Radiation Oncology Branch, National Cancer Institute, NIH, Building 10, Room B3B69, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 496-5457; Fax: (301) 480-5439.
Received 11/13/96. Accepted 3/ 5/97.
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