Qin X, Zhou H, Liu L, Gerson S L
Division of Hematology/Oncology and the Ireland Cancer Center, Case Western Reserve University, Cleveland, OH 44106-4937, USA.
Carcinogenesis. 1999 Sep;20(9):1667-73. doi: 10.1093/carcin/20.9.1667.
Mice deficient in the DNA mismatch repair (MMR) gene, PMS2, develop spontaneous thymic lymphomas and sarcomas. We have previously shown that PMS2(-/-) mice were hypersensitive to a single i.p. injection of 50 mg/kg of N-methyl-N-nitrosourea (MNU) for thymic lymphoma induction. We postulated that MNU sensitivity was due to formation of O(6)-methylguanine (O(6)-mG), which, if unrepaired by O(6)-alkylguanine DNA alkyltransferase (AGT), leads to apoptosis in MMR competent cells and O(6)-mG:T mismatches in MMR deficient cells. Tumor induction is less in MMR(+/+) mice because cells with residual DNA adducts die, whereas mutagenized cells survive in MMR(-/-) mice. Overexpression of AGT (encoded by the methylguanine DNA methyltransferase-MGMT-gene) is known to block MNU induced tumorigenesis in mice with functional MMR. To further determine the sensitivity of PMS2(-/-) mice to MNU and the protective effect of hAGT overexpression, a low dose of MNU (25 mg/kg) was studied in PMS2(-/-) mice and PMS2(-/-)/hMGMT(+) mice. No thymic lymphomas were found in MNU-treated PMS2(+/+) and PMS2(+/-) mice. At 1 year, 46% of the MNU-treated PMS2(-/-) mice developed thymic lymphoma, compared with an incidence of 25% in both untreated PMS2(-/-) mice and MNU treated PMS2(-/-)/hMGMT(+) mice. In addition, a significantly shorter latency in the onset of thymic lymphomas was seen in MNU-treated PMS2(-/-) mice. K-ras mutations were detected almost equally in the thymic lymphomas induced by MNU in both PMS2(-/-) and PMS2(-/-)/hMGMT(+) mice, but not in the spontaneous lymphomas. These data suggest that PMS(-/-) mice are hypersensitive to MNU, that there are different pathways responsible for spontaneous and MNU induced thymic lymphomas in PMS2(-/-) mice, and that overexpression of hMGMT protects the mice by blocking non-K-ras pathways.
DNA错配修复（MMR）基因PMS2缺陷的小鼠会自发发生胸腺淋巴瘤和肉瘤。我们之前已经表明，PMS2(-/-)小鼠对单次腹腔注射50mg/kg的N-甲基-N-亚硝基脲（MNU）诱导胸腺淋巴瘤高度敏感。我们推测MNU敏感性是由于O(6)-甲基鸟嘌呤（O(6)-mG）的形成，如果未被O(6)-烷基鸟嘌呤DNA烷基转移酶（AGT）修复，会导致MMR功能正常的细胞凋亡以及MMR缺陷的细胞中出现O(6)-mG:T错配。在MMR(+/+)小鼠中肿瘤诱导较少，因为带有残留DNA加合物的细胞会死亡，而诱变细胞在MMR(-/-)小鼠中存活。已知AGT（由甲基鸟嘌呤DNA甲基转移酶-MGMT-基因编码）的过表达可阻断功能性MMR的小鼠中MNU诱导的肿瘤发生。为了进一步确定PMS2(-/-)小鼠对MNU的敏感性以及hAGT过表达的保护作用，在PMS2(-/-)小鼠和PMS2(-/-)/hMGMT(+)小鼠中研究了低剂量的MNU（25mg/kg）。在接受MNU处理的PMS2(+/+)和PMS2(+/-)小鼠中未发现胸腺淋巴瘤。在1岁时，46%接受MNU处理的PMS2(-/-)小鼠发生了胸腺淋巴瘤，相比之下，未处理的PMS2(-/-)小鼠和接受MNU处理的PMS2(-/-)/hMGMT(+)小鼠的发病率均为25%。此外，在接受MNU处理的PMS2(-/-)小鼠中，胸腺淋巴瘤发病的潜伏期明显更短。在PMS2(-/-)和PMS2(-/-)/hMGMT(+)小鼠中，由MNU诱导的胸腺淋巴瘤中几乎同等程度地检测到K-ras突变，但在自发淋巴瘤中未检测到。这些数据表明，PMS(-/-)小鼠对MNU高度敏感，在PMS2(-/-)小鼠中，自发和MNU诱导的胸腺淋巴瘤有不同的途径，并且hMGMT的过表达通过阻断非K-ras途径保护小鼠。
