Microsatellite instability, chemosensitivity and mutant frequency in a series of 1,2-dimethylhydrazine induced murine colon adenocarcinoma models
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Updated: Oct 29, 2026
Quantification of Colonic Stem Cell Mutations
Published on: September 25, 2015
M J Thompson1, R Slack, J A Double
1Clinical Oncology Unit, University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK.
Abstract:
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.
Insights
DNA mismatch repair defects in colon adenocarcinoma may affect chemotherapy response. This study found no direct link between microsatellite instability and chemoresistance in mouse or human cell lines.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- DNA mismatch repair (MMR) deficiency is observed in various cancers, including colorectal adenocarcinoma, leading to microsatellite instability (MSI).
- MMR defects can influence tumor response to specific anti-cancer agents, highlighting potential clinical relevance.
Purpose of the Study:
- To investigate microsatellite instability in murine colon adenocarcinoma models.
- To explore the association between MSI, mutant frequency, and chemo-sensitivity in both mouse and human adenocarcinoma cell lines.
Main Methods:
- Eight 1,2-dimethylhydrazine-induced murine colon adenocarcinoma models were analyzed for MSI across four microsatellite regions.
- Loss of heterozygosity (LOH) was assessed, with a focus on the D11MIT4 locus near the p53 tumor suppressor gene.
- In vitro chemo-sensitivity assays were performed on four mouse models and four human adenocarcinoma cell lines, comparing responses to cisplatin and 6-thioguanine.
Main Results:
- Four of the eight murine tumor models exhibited low-level MSI.
- LOH was detected in 5/8 tumors, indicating its potential role in tumor development.
- Two human cell lines (MAC26 and MAC16) showed increased chemoresistance to cisplatin, but not 6-thioguanine.
- No significant association was found between MSI and chemo-sensitivity in either the mouse or human cell lines.
Conclusions:
- Allelic loss, particularly near the p53 locus, may be a common event in the carcinogenesis of these murine colon adenocarcinoma models.
- Despite the known link between MMR defects and MSI, this study did not establish a direct correlation between MSI and chemo-sensitivity in the evaluated cell lines.
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