Nobel therapeutic strategy based on deficient expression of DNA repair gene in gastrointestinal cancers.

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Expression of O^6 methylguanine DNA methyltransferase (MGMT) and mismatch repair gene hMLH1 was frequently lost in gastrointestinal cancer including biliary tract, hepatocellular, gastric and colorectal cancers. We previously reported significant correlation between deficient expression of MGMT, hMLH1 gene and poor outcome in biliary tract, hepatocellular and gastric cancer patients. MGMT is known as repair enzyme against alkylating modifications of cellular DNA. Recent reports using MGMT/hMLH1 knockout mice demonstrated that mice with MGMT(-) /hMLH1(+) was highly sensitive to alkylating agent MNU, leading to death by severe myelosuppression. We hypothesized that drug sensitivity to alkylating anticancer drug might depend on expression status of MGMT and hMLH1 in cancer cells. In this research project, we attempted to build a novel therapeutic strategy using alkylating agents, in which the drug sensitivity is predictable by MGMT/hMLH1 gene expression before chemotherapeutic treatment.1 … More (2003) Using 6 biliary tract acncer cell lines, we correlated expression pattern of MGMT/hMLH1 gene with drug sensitivity to alkylating agent MNU. As a result, 2 cell lines with MGMT(-)/hMLH1(+) was the most highly sensitive to MNU, compared with resultant cells with MGMT(+)/hMLH1(+) or MGMT(-)/hMLH1(-). This association was also found in xenograft tumor on nude mice. These results suggested that expression status of MGMT/hMLH1 is a marker for predicting drug sensitivity to alkylating agents. Furthermore, we found MGMT expression was suppressed under cisplatin with low dose concentration. This result indicated a novel biochemical modulation therapy using alkylating agents, where MGMT positive cancer cellscould be altered to MGMT deficient type by cisplatin treatment.2 (2004) It was recently reported that loss of MGMT and hMLH1 expressions in cancer were mainly caused by epigenetic gene methylation. Thus we analyzed methylation status of MGMT, hMLH1 in biliary tract cancer tissues. We demonstrated a significant correlation between MGMT methylation and reduced expression of MGMT protein. This result suggested MGMT methylation in cancer cells, which leading to the reduced protein expression, is molecular marker predicting drug sensitivity to alkylating agents.3 (2005) We found significant correlation between hMLH1 (-) status and high sensitivity to topoisomerase 1 inhibitor CPT-11 in biliary trac cancer cells. We confirmed the association by hMLH1 siRNA transfection to cancer cells with hMLH1 (+). Besides, we found DPD deficient cell line among 6 biliary tract cancer cells. We elucidated epigenetic modification of DPD gene occured in this cell line. DPD is known as an important enzyme determinating sensitivity to 5-FU. Thus we indicated deficient DPD expression in gastrointestinal cancer might be molecular marker predicting drug sensitivity to 5-FU. In gastric cancer cell lines and tissues, we observed significant correlation of CHFR gene methylation with high sensitivity to mictotubule inhibitor, Taxan. These results contributed to enriching molecular marker for selecting various anticancer drugs. We are willing to develop this research project and apply to our protocol for clinical cancer treatment. Less