title: Mammalian DNA topoisomerase I mediates the enhancement of radiation cytotoxicity by camptothecin derivatives.
abstract: The role of DNA topoisomerase I as a biochemical mediator of radiosensitization 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 microM, 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 1-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.
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: A Y
authors.initials: AY
authors.lastname: Chen
authors.forename: P
authors.initials: P
authors.lastname: Okunieff
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
authors.forename: J B
authors.initials: JB
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002453:Cell Cycle; D002478:Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004264:DNA Topoisomerases, Type I / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001562:Benzimidazoles; D011838:Radiation-Sensitizing Agents; D004247:DNA; D004264:DNA Topoisomerases, Type I; C017807:bisbenzimide ethoxide trihydrochloride; D002166:Camptothecin