Induction of radiosensitization by indolocarbazole derivatives: the role of DNA topoisomerase I.
DNA topoisomerase I (TOP1) mediates the induction of radiosensitization (RS) by camptothecin derivatives in mammalian cells. Many indolocarbazole (INDO) derivatives have been shown to induce TOP1-mediated DNA damage (T1DD). In the current study, we characterized the cytotoxic and radiosensitizing activities of six INDO derivatives in relation to their efficiencies to induce T1DD. Evaluated by clonogenic survival assay, the INDO derivatives F1, F5, and F7, but not F43, F44, or F71, were shown to induce significant levels of RS in the human breast cancer MCF-7 cells at noncytotoxic concentrations. Analyzed by the single-hit multitarget (SHMT) model, F1, F5, and F7, like camptothecin, induce RS by obliterating the "shoulder" of radiation survival curve. In contrast to the Chinese hamster DC3F cells, the TOP1 mutant DC3F/C10 cells demonstrated cross-resistance to the cytotoxicity of F7 and the induction of RS by F7 and F1. The efficiencies to induce T1DD were determined by 1) drug-stimulated TOP1 cleavage assay in vitro and 2) K(+)-SDS coprecipitation assay in vivo. These compounds exhibited varying efficiencies in inducing T1DD with the following order: F71, F7 > F44, F1 > F5 > F43. It is surprising that the individual efficiency of these compounds to induce T1DD correlates well with their individual cytotoxicity but not RS activity. Taken together, our data demonstrate that certain, but not all, INDO derivatives capable of inducing T1DD can induce RS in mammalian cells. The INDO derivatives F1, F5, and F7 have the potential to be developed as a new class of radiation sensitizers.
Department of Radiation Oncology, UC Davis Medical Center, 4501 "X" Street, G-126, Sacramento, CA 95817, USA. aychen@ucdavis.edu
Allan Y
AY
Chen
Shyh-Jen
SJ
Shih
Michael
M
Hsiao
Mace L
ML
Rothenberg
Michelle
M
Prudhomme
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D016466:CHO Cells; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D002227:Carbazoles; D007211:Indoles; D011838:Radiation-Sensitizing Agents; D004264:DNA Topoisomerases, Type I