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Liver Tumor Development (liver + tumor_development)
Selected AbstractsRapamycin delays tumor development in murine livers by inhibiting proliferation of hepatocytes with DNA damage,HEPATOLOGY, Issue 2 2009Laura Elisa Buitrago-Molina In this study, everolimus (RAD001) was used to determine the role of mammalian target of rapamycin (mTOR) in hepatocarcinogenesis. We show that RAD001 effectively inhibits proliferation of hepatocytes during chronic liver injury. Remarkably, the ability of RAD001 to impair cell cycle progression requires activation of the DNA damage response; loss of p53 significantly attenuates the antiproliferative effects of mTOR inhibition. RAD001 modulates the expression of specific cell cycle,related proteins and the assembly of cyclin,cyclin-dependent kinase complexes to prevent cell cycle progression. Furthermore, RAD001 sustains the apoptosis sensitivity of hepatocytes during chronic liver injury by inhibiting p53-induced p21 expression. Long-term treatment with RAD001 markedly delays DNA damage,induced liver tumor development. Conclusion: We provide evidence that mTOR inhibition has a substantial effect on sequential carcinogenesis and may offer an effective strategy to delay liver tumor development in patients at risk. (HEPATOLOGY 2009;50:500,509.) [source] Levels of 4-aminobiphenyl-induced somatic H- ras mutation in mouse liver DNA correlate with potential for liver tumor development,MOLECULAR CARCINOGENESIS, Issue 4 2005Barbara L. Parsons Abstract The utility of liver H- ras codon 61 CAA to AAA mutant fraction as a biomarker of liver tumor development was investigated using neonatal male mice treated with 4-aminobiphenyl (4-ABP). Treatment with 0.1, 0.3, or 1.0 ,mol 4-ABP produced dose-dependent increases in liver DNA adducts in B6C3F1 and C57BL/6N mice. Eight months after treatment with 0.3 ,mol 4-ABP or the DMSO vehicle, H- ras codon 61 CAA to AAA mutant fraction was measured in liver DNA samples (n,=,12) by allele-specific competitive blocker-polymerase chain reaction (ACB-PCR). A significant increase in average mutant fraction was found in DNA of 4-ABP-treated mice, with an increase from 1.3,×,10,5 (control) to 44.9,×,10,5 (treated) in B6C3F1 mice and from 1.4,×,10,5 to 7.0,×,10,5 in C57BL/6N mice. Compared with C57BL/6N mutant fractions, B6C3F1 mutant fractions were more variable and included some particularly high mutant fractions, consistent with the more rapid development of liver foci expected in B6C3F1 mouse liver. Twelve months after treatment, liver tumors developed in 79.2% of 4-ABP-treated and 22.2% of control B6C3F1 mice; thus measurement of H- ras mutant fraction correlated with subsequent tumor development. This study demonstrates that ACB-PCR can directly measure background levels of somatic oncogene mutation and detect a carcinogen-induced increase in such mutation. Published 2005 Wiley-Liss, Inc. [source] Protection against Malignant Progression of Spontaneously Developing Liver Tumors in Transgenic Mice Expressing O6 -Methylguanine-DNA MethyltransferaseCANCER SCIENCE, Issue 11 2000Xiusheng Qin To study the effect of O6 -methylguanine-DNA methyltransferase (MGMT) on carcinogenesis, we have previously generated MGMT transgenic mice overexpressing the bacterial MGMT gene, ada, and demonstrated that high MGMT levels in the liver suppress induction of liver tumors after treatment with an alkylating hepatocarcinogen. To examine the effects of life-long elevation of MGMT activity on mouse spontaneous liver tumor development, ada-transgenic and control nontransgenic mice were compared. We also examined mutations at codon 61 of the H-ras oncogene, reported as a hot spot in mouse liver tumors, using a direct DNA sequencing method. The results revealed no significant difference in tumor incidence or mutation spectrum, but interestingly, ada-transgenic mice were found to have fewer malignant tumors and survived longer, indicating a possible protective role of MGMT against malignant conversion. [source] | ||||||||||