Microsatellite instability, chemosensitivity and mutant frequency in a series of 1,2-dimethylhydrazine induced murine colon adenocarcinoma models.
Loss of DNA mismatch repair has been described in a number of tumour types such as colorectal adenocarcinoma and leads to microsatellite instability. This may have clinical relevance due to mismatch repair defects altering chemosensitivity towards certain classes of anti-tumour agent. This study has examined microsatellite instability of eight murine colon adenocarcinoma tumour models induced by 1,2-dimethylhydrazine. Four microsatellite regions were examined suggesting that four of the tumour models exhibit a low level of microsatellite instability. Loss of heterozygosity was found in 5/8 tumours, suggesting that allelic loss may be a relatively common step in the carcinogenesis of these tumour models. Three of the allelic losses involved the D11MIT4 locus which is situated very close to the p53 tumour suppressor locus. Four tumour models are routinely cultured in vitro and these were used to examine whether there was any association between microsatellite instability, mutant frequency and chemo-sensitivity of these tumour models, comparing them with four human adenocarcinoma cell lines of known mismatch repair status. Two cell lines (MAC26 and MAC16) were found to be more chemoresistant towards cisplatin but not 6-thioguanine. No association was found between microsatellite instability and chemosensitivity for either the human or mouse cell lines.
Clinical Oncology Unit, University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK.
M J
MJ
Thompson
R
R
Slack
J A
JA
Double
M C
MC
Bibby
D019813:1,2-Dimethylhydrazine; D000230:Adenocarcinoma / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002273:Carcinogens; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics*; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D019656:Loss of Heterozygosity; D051379:Mice; D018895:Microsatellite Repeats; D009154:Mutation; D013866:Thioguanine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D002273:Carcinogens; D004273:DNA, Neoplasm; D013866:Thioguanine; D019813:1,2-Dimethylhydrazine; D002945:Cisplatin