INDUCTION OF DNA-DAMAGE, INHIBITION OF DNA-SYNTHESIS, AND SUPPRESSIONOF C-MYC EXPRESSION BY THE TOPOISOMERASE-I INHIBITOR, CAMPTOTHECIN, IN MCF-7 HUMAN BREAST-TUMOR CELLS

Previous work from this laboratory has demonstrated an association bet ween the suppression of c-myc expression and the antiproliferative act ivity of both topoisomerase II inhibitors and ionizing radiation in MC F-7 breast tumor cells. These findings suggested that suppression of c -myc expression could be related to the induction of DNA damage in thi s cell line. The present studies were designed to determine whether th e inhibition of topoisomerase I (and the consequent induction of DNA s trand breaks) would also result in the suppression of c-myc expression . At camptothecin concentrations of 1 mu M and below, there was no det ectable damage (single or double-strand breaks) in bulk DNA or suppres sion of c-myc expression. At camptothecin concentrations of 5, 10, and 25 mu M, where suppression of c-myc expression was observed, strand b reaks in bulk DNA were also detected. These findings are consistent wi th the idea that suppression of c-myc expression could be a component of the DNA damage response pathway in MCF-7 breast tumor cells. In con trast to the absence of detectable damage to bulk DNA or suppression o f c-myc expression at the lower concentrations of camptothecin, DNA sy nthesis was inhibited over the entire range of drug concentrations and demonstrated a strong correspondence with growth inhibition. These ob servations support the concept that growth inhibition of MCF-7 cells b y camptothecin is closely related to the early suppression of DNA synt hesis. (C) 1998 Elsevier Science Inc.