Msh2 deficiency attenuates but does not abolish thiopurine hematopoietic toxicity in Msh2-/- mice
Msh2 deficiency attenuates but does not abolish thiopurine hematopoietic toxicity in Msh2-/- mice
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DOI：
10.1124/mol.64.2.456
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发表时间：
2003-08-01
影响因子：
3.6
通讯作者：
Evans, WE
中科院分区：
文献类型：
--
作者：
Krynetskaia, NF;Brenner, TL;Evans, WE
MSH2蛋白是错配修复系统的主要组成部分，研究发现白血病细胞与新诊断的急性淋巴细胞白血病儿童的MSH2蛋白含量相差10倍，其中有一部分患者（17%）检测不到MSH2蛋白。因此，我们使用小鼠Msh2敲除模型来阐明Msh2蛋白表达在确定硫嘌呤造血细胞毒性中的体内重要性。巯基嘌呤（mercaptopurine, 30 mg/kg/d）治疗14天后，Msh2（+/+）和Msh2（+/-）小鼠与Msh2（-/-）小鼠相比，循环白细胞减少显著（p < 0.002）。同样，红细胞计数的减少在至少有一个功能性Msh2等位基因的小鼠中更为显著。MP剂量超过50 mg/kg/天，持续14天导致治疗相关死亡，但Msh2（-/-）小鼠具有显著的生存优势（p = 0.02）。与来自Msh2（-/-）小鼠的mef相比，来自Msh2（+/+）小鼠的小鼠胚胎成纤维细胞（mef）对MP的敏感性也有所增加（IC50, 3.8 +/- 0.1 μ M比11.9 +/- 1.3 μ M, p < 0.001）。MP处理后，各Msh2基因型小鼠和mef的脱氧硫代鸟苷并入DNA的情况相似。在Msh2(+/+) mef中发现了含有GT-或G(S) t - dna -核蛋白复合物的Msh2，但在Msh2(-/-) mef中没有。总之，这些发现证实了巯基嘌呤治疗后体内的造血毒性减弱，但MSH2缺乏并未消除。
The amount of MSH2 protein, a major component of the mismatch repair system, was found to differ >10-fold in leukemia cells from children with newly diagnosed acute lymphoblastic leukemia, with a subgroup of patients (17%) having undetectable MSH2 protein. We therefore used a murine Msh2 knockout model to elucidate the in vivo importance of MSH2 protein expression in determining thiopurine hematopoietic cytotoxicity. After mercaptopurine ( MP) treatment ( 30 mg/kg/day for 14 days), there was a significantly greater decrease in circulating leukocytes in Msh2(+/+) and Msh2(+/-) mice when compared with Msh2(-/-) mice ( p < 0.002). Likewise, the decrease in erythrocyte counts was more prominent in mice with at least one functional Msh2 allele. MP doses of more than 50 mg/kg/day for 14 days resulted in treatment-related deaths, but Msh2(-/-) mice had a significant survival advantage ( p = 0.02). Murine embryonic fibroblasts (MEFs) from Msh2(+/+) mice also exhibited increased sensitivity to MP when compared with MEFs from Msh2(-/-) mice (IC50, 3.8 +/- 0.1 mu M versus 11.9 +/- 1.3 mu M, p < 0.001). After MP treatment, deoxythioguanosine incorporation into DNA was similar in mice and MEFs with each of the Msh2 genotypes. Electromobility shift assay experiments identified an Msh2-containing GT- or G(S)T-DNA-nuclear protein complex in Msh2(+/+) but not Msh2(-/-) MEFs. Together, these findings establish that hematopoietic toxicity in vivo after treatment with mercaptopurine is attenuated but not abolished by MSH2 deficiency.