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 to topo I expression vary widely between and within tumour types and the basis for the 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 or 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, (r(s)=0.92), and inversely correlated to sensitivity to a 1 h exposure to SN38 (r(s)=-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.