Variation in topoisomerase I gene copy number as a mechanism for intrinsic drug sensitivity.

Abstract

DNA topoisomerase I (topo I) is the principle target for camptothecin and its derivatives such as SN38. Levels of topo I expression vary widely between and within tumour types and the basis for this is poorly understood. We have used fluorescence in situ hybridisation to detect the topo I locus in a panel of breast and colon cancer cell lines. This approach has identified a range of topo I gene copies from 1 to 6 between the cell lines as a result of DNA amplification, polysomy and isochromosome formation. Topo I gene copy number was highly correlated with topo I expression, (rs = 0.92), and inversely correlated to sensitivity to a 1 h exposure to SN38 (rs = -0.904). This illustrates the significant impact of altered topo I gene copy number on intrinsic drug sensitivity and influences potential mechanisms for acquisition of drug resistance.

• Authors: H L McLeod, W N Keith
• Journal: British journal of cancer (Br J Cancer) Vol. 74 Issue 4 Pg. 508-12 (Aug 1996) ISSN: 0007-0920 [Print] England
• PMID: 8761363 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Nuclear Proteins
• Irinotecan
• DNA Topoisomerases, Type I
• Camptothecin

Topics

• Antineoplastic Agents, Phytogenic (toxicity)
• Breast Neoplasms
• Camptothecin (analogs & derivatives, toxicity)
• Cell Line
• Cell Survival (drug effects)
• Colonic Neoplasms
• DNA Topoisomerases, Type I (biosynthesis, genetics)
• Drug Resistance, Neoplasm
• Female
• Gene Amplification
• Gene Expression
• Genetic Variation
• Humans
• In Situ Hybridization, Fluorescence
• Irinotecan
• Karyotyping
• Kinetics
• Nuclear Proteins (metabolism)
• Tumor Cells, Cultured