Variation in topoisomerase I gene copy number as a mechanism for intrinsic drug sensitivity.
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.
McLeod
H L
HL
CRC Department of Medical Oncology, University of Glasgow, UK.
Keith
W N
WN
D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D001943:Breast Neoplasms; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification; D015870:Gene Expression; D014644:Genetic Variation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D000077146:Irinotecan; D007621:Karyotyping; D007700:Kinetics; D009687:Nuclear Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D009687:Nuclear Proteins; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin