| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2001: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Research Abstract |
O^6-Methylguanine-DNA methyltansferase(MGMT) is a DNA repair enzyme that transfers methyl groups from O^6-Methylguanine to itself When MGMT expression is impaired, the O^6-Methylguanine mispairs with thymine during DNA replication, resulting in G:C→A:T transitional mutation in DNA. We have previously demonstrated that the deficient expression of MGMT was correlated with a poor prognosis of patients with biliary tract, hepatocellular and gastric carcinoma in immunohistochemical study. We consequently prompted two possible hypotheses how MGMT loss contributes to tumor progression. One is that MGMT loss in carcinoma may cause an accumulation of DNA mutation in oncogenes and tumor suppressor genes, which brings about tumor progression leading to poor prognosis. Thus, we investigated using gall bladder (GB) carcinoma specimens whether or not gene mutation including K-ras, p53 and β-catenin correlates with MGMT status, and assessed whether the gene mutation exhibit a G:C→A:T transition origi
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nated from MGMT loss. DNA seguencing study defined that frequency of gene mutations were 11.5% in K-ras, 40% in p53 and 10% in β catenin. Although significant correlation between MGMT loss and DNA mutation in the candidate genes, G:C→A:T transition in K-ras gene was observed in several specimens with MGMI loss. Another possible mechanism is by epigenetic DNA modification, that hypermethylation on promoter region may simultaneously occur in MGMT as well as other genes. Indeed, we found that MGMT gene silencing was caused by CpG methylation of the MGMT promoter in Hepatocellular carcinoma. We are examining in GB carcinoma whether promoter hypermetylation may occur in MGMT, E-cadherin and p16 genes by methylation specific PCR method. Currently, we have revealed that GB carcinoma cell line with MGMT(-)hMLH1(+) exerted high sensitivity and apoptosis to alkylating drug. In this study, we propose that abortive mismatch repair function in addition to MGMT loss contributes to cytotoxic effects of alkylating agents. We are attempting molecular targetting chemotherapy using alkylating agents based on MGMT and hMLH1 status. Less
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