| Budget Amount *help |
¥10,000,000 (Direct Cost: ¥10,000,000)
Fiscal Year 1999: ¥10,000,000 (Direct Cost: ¥10,000,000)
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| Research Abstract |
Oxidative DNA damage is thought to contribute to carcinogenesis, aging, and neurological degeneration. Studies have shown that oxidative DNA damage accumulates in cancerous tissue. For example, higher levels of oxidative base damage were observed in lung cancer tissue compared with surrounding normal tissue. Further, the cumulative risk of cancer increases dramatically with age in humans. In genreal terms cancer can be regarded as a degenerative disease of ageing. There is evidence for the accumulation of oxidative DNA damage with age based on studies mainly measuring an increase in 8-oxoG.
8-Oxo-7, 8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) is formed in the nucleotide pool of a cell during normal cellular metabolism. When incorporated into DNA, 8-oxo-dGTP causes mutation. Organisms posseces 8-oxo-dGTPase, an enzyme that specifically degrades 8-oxo-dGTP to 8-oxo-dGMP.By means of gene targeting, we established mouse lines deficient in the MTH1 gene, and 8-oxo-dGTPase activi
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ty. An approximately 2-fold higher frequency of spontaneous mutations in the HPRT gene was observed in two independently isolated MTH1^<-/-> ES cell lines, compared with the value of MTH1^<+/+> cells. We then examined susceptibility of the derived mutant mice to spontaneous tumorigenesis. Wild type or mutant mice consisting of approximately 50 male and 50 female were maintained under SPF conditions and necropsied after 1.5 years. No significant difference in survival rates of MTH1^<+/+> and MTH1^<-/-> mice. However, pathological examination revealed a statistically significant difference in the incidence of tumors. A distinct difference in the frequency of tumor formation in lungs between wild-type and mutant mice was observed while more tumors were likely to be formed in the stomach and in liver of MTH1^<-/-> mice as well. 8-Oxo-dGTPase appears to play an important role to protect animals from the spontaneous tumorigenesis caused by the oxygen-induced DNA damage. To study the enhancing effect of chronic inflammation in carcinogenesis, we investigated the spontaneous gastric carcinogenesis in MTH1 deficient mice infected with Helicobacter pylori (H.P.). MTH1^<-/-> mouse and wild type were inocculated intragastrically with H.pylori. After 1.5 year of obserbvation, chrronic gastritis was observed histologically in infected mouse of both MTH1 status. The incidence rate of hyperplastic elevated lesion was augmented by H.P.infection. Moreover, the incidence rate of atypical hyperplastic lesion was augmented especially in MTH1^<-/-> mouse infected with H.pylori. Less
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