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 microM 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 microM, 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.

• Authors: P T Jain, F A Fornari, J K Randolph, M S Orr, D A Gewirtz
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 55 Issue 8 Pg. 1263-9 (Apr 15 1998) ISSN: 0006-2952 [Print] England
• PMID: 9719482 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents, Phytogenic
• Enzyme Inhibitors
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors
• DNA
• Camptothecin

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Breast Neoplasms
• Camptothecin (pharmacology)
• Cell Division (drug effects)
• DNA (biosynthesis, drug effects)
• DNA Damage
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, myc (drug effects, genetics)
• Humans
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors
• Tumor Cells, Cultured