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Comparative Genomic Hybridization Analysis of Chromosomal Alterations Induced by the Development of Resistance to Thymidylate Synthase Inhibitors¹

Departments of Medicine and Therapeutics [P. H. R., S. M., J. C., H. L. M.] and Medical Genetics [D. A. J. S., N. E. H.], Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland AB25 2ZD; and Department of Oncology, Queen's University of Belfast, Belfast, Northern Ireland [P. G. J.], United Kingdom

Acquired resistance to chemotherapy is a major obstacle to the successful treatment of cancer. In the past, technical limitations prevented the detection of genetic alterations associated with such resistance on a genome-wide scale. This study evaluated comparative genomic hybridization (CGH) as a tool to detect candidate regions of the genome associated with chemoresistance. Using a variation of conventional CGH, DNA from cell lines that were resistant to thymidylate synthase inhibitors (raltitrexed and 5-fluorouracil) and their sensitive parent cells were evaluated. In MCF-7 and H630 cells that were resistant to raltitrexed, only a single region of change (18p gain) was apparent. The third cell line, H630R10, which was resistant to 5-fluorouracil, had changes in several genomic regions following the acquisition of resistance, including 18p gain. Gain in the chromosomal region containing the thymidylate synthase gene (18p11.32) was detected by CGH in all three resistant cell lines. However, additional novel regions of interest were identified in the cells that were resistant to 5-fluorouracil. These results suggest that CGH is of potential use in the detection of regions of the genome involved in chemoresistance.

¹ This work was supported in part by a University of Aberdeen Research Consortium studentship, a Medical Research Council studentship, the University of Aberdeen Medical Faculty, and an Aberdeen Royal Infirmary endowment grant.

² To whom requests for reprints should be addressed, at Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, AB25 2ZD, United Kingdom. Phone: 44 1224 681818 ext. 52730; Fax: 44 1224 273066; E-mail: h.l.mcleod@abdn.ac.uk.

Received 7/15/98. Accepted 9/30/98.

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