Colorectal cancer (CRC) cell lines displaying microsatellite instability (MSI) are resistant to 5-fluorouracil in vitro, which can be overcome by restoring DNA mismatch repair (MMR) competence. Furthermore, elevated levels of Bcl-2 protein confers cytotoxic drug resistance to tumour cell lines. We examined the expression of Bcl-2 and two MMR proteins (hMLH1 and hMSH2) in advanced CRC patients, to determine their mutual relationship, association to therapeutic response and impact on disease outcome. Tumour samples from 73 CRC patients who were treated in advanced stage with either irinotecan alone or in combination with 5-FU/leucovorin, were analysed for expression of Bcl-2, hMLH1 and hMSH2 using immunohistochemistry. Bcl-2 expression was closely correlated with hMLH1 and hMSH2 expression (negative-weak/moderate-strong) (p=0.01). Bcl-2/MMR expression was significantly (p=0.030 for whole series; p=0.018 for the 5-FU-treated cases) related to the response to treatment; tumours with low levels of both Bcl-2 and MMR responded better (n=18/31, 58%) than those with high Bcl-2 and MMR (n=3/16, 18%). Patients with high Bcl-2/MMR expression had a significantly longer DFS (47 vs. 11 months, n=26) than those with low Bcl-2/MMR index (p=0.005). Bcl-2/MMR index was not significantly related to disease-specific survival or survival with metastases. The present data suggest that MSI patients with low Bcl-2/MMR demonstrate a significantly shorter DFS, whereas patients with high expression of the two markers obtain the greatest benefit from 5-FU-based chemotherapy.
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Adaptor Proteins, Signal Transducing, Antineoplastic Agents, Colorectal Neoplasms, Disease-Free Survival, Female, Gene Expression, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Male, Microsatellite Instability, Middle Aged, MutL Protein Homolog 1, MutS Homolog 2 Protein, Nuclear Proteins, Prognosis, Proto-Oncogene Proteins c-bcl-2