Genomic imbalances associated with acquired resistance to platinum analogues.
During the past several years, a panel of human tumor cell lines (predominantly ovarian) with acquired resistance to cisplatin, the orally bioavailable analogue JM216, and the structurally hindered analogue AMD473, has been established and characterized for underlying mechanisms of resistance. We have examined these resistant cell lines for gains and losses of DNA associated with the acquisition of resistance using the molecular cytogenetic technique of comparative genomic hybridization. Our comparison of three analogues has shown the most frequently observed changes to include amplification of 4q (5/7) and 6q (5/7), followed by amplification of 5q (3/7). We have defined four minimal common overrepresented regions, two each on 4q and 6q, which are potential loci of genes associated with platinum analogue resistance. Additional consistent abnormalities appear to be associated with cell lines sharing specific resistance mechanisms. For example, amplification of 12q was observed in the CH1 lines made respectively resistant to JM216 and AMD473 in which increased DNA repair appears to be a major mechanism of resistance for both agents. Hence, these comparative genomic hybridization studies have identified distinct chromosomal aberrations which may correlate with defined mechanisms of resistance and contain hitherto unrecognized genes that may provide targets for future therapeutic intervention.
Department of Oncology, McGill University, Montreal, Quebec, Canada. leylandj@med.mcgill.ca
B
B
Leyland-Jones
L R
LR
Kelland
K R
KR
Harrap
L R
LR
Hiorns
D000970:Antineoplastic Agents / Q000494:pharmacology; D002869:Chromosome Aberrations / Q000235:genetics; D002875:Chromosomes / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016678:Genome; D006801:Humans; D009693:Nucleic Acid Hybridization; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010984:Platinum / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C110525:amminedichloro(2-methylpyridine)platinum(II); D010984:Platinum; C081294:satraplatin; D002945:Cisplatin