Detection-evaluation systems for carcinogens with the use of gene-defective mice

Mice with mutation in both alleles of the Mgmt and the Mlh1 genethe former encoding a DNA repair methyltransferase and the latter a protein functioning at earlystep of mismatch repair，are as resistant to the killing action of alkylating agents as are wild-type mice. These miceielded a large number of tumors, when exposed to alkylating carcinogens，但是这个角色已经取代了他们也应该是一个relatively high level of spontaneoustumorigenistiy,as the consequence of the defect in mismatch repair. This complexity is now resolved by introducingthe Mlh1+/- mutation, instead of Mlh1-/-，in these methyltransferase-deficient mice. Mlmt - 1-/- mice Mlh1 - mice +/- mice with about half theamount of MLH1 protein as Mgmt - 1-/- D1 MLH1 - +/+ D1 mice，were resistant to the killing action of n methyl- n -nitrosourea （MNU）提高30毫克/公斤的体重水平。八个星期后，这个体重增加。40% of MNU-treated Mgmt - D1-/- D1 Mlh1 - D1+/- D1 mice had thymic lymphoma and there was no tumorin these mice not given the treatment. It seems that the cellular content of MLH1 protein is acritical factor for determining if damaged cells enter into either one of the two pathways，leading to mutation induction and to apototic cell death. Loss of Mlh1表达式经常出现observed with tumors of Mgmt - 1-/- D1 Mlh1 - D1+/- D1 mice，and this might be related to progression of the tumors。

Mice with mutation in both alleles of the Mgmt and the Mlh1 gene, the former encoding a DNA repair methyltransferase and the latter a protein functioning at an early step of mismatch repair, are as resistant to the killing action of alkylating agents as are wild-type mice. These mice yielded a large number of tumors, when exposed to alkylating carcinogens, but this characteristic was subdued since they also showed a relatively high level of spontaneous tumorigenistiy, as the consequence of the defect in mismatch repair. This complexity is now resolved by introducing the Mlh1+/- mutation, instead of Mlh1-/-, in these methyltransferase-deficient mice. MlmtィイD1-/-ィエD1 Mlh1ィイD1+/-ィエD1 mice with about half the amount of MLH1 protein as MgmtィイD1-/-ィエD1 Mlh1ィイD1+/+ィエD1 mice, were resistant to the killing action of N-methyl-N-nitrosourea (MNU), up to the level of 30 mg/kg of body weight. Eight weeks after exposure to this dose of MNU, 40% of MNU-treated MgmtィイD1-/-ィエD1 Mlh1ィイD1+/-ィエD1 mice had thymic lymphoma and there was no tumor in these mice not given the treatment. It seems that the cellular content of MLH1 protein is a critical factor for determining if damaged cells enter into either one of the two pathways, leading to mutation induction and to apototic cell death. Loss of Mlh1 expression was frequently observed with tumors of MgmtィイD1-/-ィエD1 Mlh1ィイD1+/-ィエD1 mice, and this might be related to progression of the tumors.