Induction of DNA Damage, Inhibition of DNA Synthesis, and Suppression of c- myc Expression by the Topoisomerase I Inhibitor, Camptothecin, in MCF-7 Human Breast Tumor Cells

Abstract

Previous work from this laboratory has demonstrated an association between the suppression of c- myc expression and the antiproliferative activity of both topoisomerase II inhibitors and ionizing radiation in MCF-7 breast tumor cells. These findings suggested that suppression of c- myc expression could be related to the induction of DNA damage in this cell line. The present studies were designed to determine whether the inhibition of topoisomerase I (and the consequent induction of DNA strand breaks) would also result in the suppression of c- myc expression. At camptothecin concentrations of 1 μM and below, there was no detectable damage (single- or double-strand breaks) in bulk DNA or suppression of c- myc expression. At camptothecin concentrations of 5, 10, and 25 μM, where suppression of c- myc expression was observed, strand breaks in bulk DNA were also detected. These findings are consistent with 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 contrast to the absence of detectable damage to bulk DNA or suppression of c- myc expression at the lower concentrations of camptothecin, DNA synthesis was inhibited over the entire range of drug concentrations and demonstrated a strong correspondence with growth inhibition. These observations support the concept that growth inhibition of MCF-7 cells by camptothecin is closely related to the early suppression of DNA synthesis.