Several comparative genomic hybridization (CGH) analyses have been used to detect the genetic aberrations associated with resistance to fluoropyrimidine, including fluorouracil (5FU). Gain of 18p and Losses of 3q and 3p were common chromosomal aberrations in these studies. 18p gain or amplification was concordantly observed. Thymidylate synthase (TS) gene, encoding for important target enzyme in 5FU metabolism was mapped at 18p. Therefore, these suggested that those genetic changes were one of the ways to induce overexpression of TS and acquire drug resistance. Previous studies reported that loss of 3q could induce decreased orotate phosphoribosyl transferase (OPRT) activity, which is one of bifunction of uridine monophosphate (UMP) synthase gene (3q13). It was also reported that the introduction of chromosome 3, which contains hMLH1 mapped on 3p21.3 to DNA mismatch repair deficient cells with homozygous hMLH1 mutation,reduced the resistance to DNA damaging agents. These results suggested that the loss of 3q and 3p might be a genetic change to decrease fluoropyrimidine cytotoxic response in cancer cells. These results indicate that chromosomal aberrations identified by CGH could explain, at least in part, acquired fluoropyrimidine resistance.
