Increasing DNA repair methyltransferase levels via bone marrow stem cell transduction rescues mice from the toxic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea, a chemotherapeutic alkylating agent
Increasing DNA repair methyltransferase levels via bone marrow stem cell transduction rescues mice from the toxic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea, a chemotherapeutic alkylating agent
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DOI：
10.1073/pnas.93.1.206
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发表时间：
1996-01-09
影响因子：
11.1
通讯作者：
Samson, L
中科院分区：
文献类型：
--
作者：
Maze, R;Carney, JP;Samson, L
氯乙基亚硝基脲（CNU）烷化剂通常用于癌症化疗，但其有效性受到严重骨髓毒性的限制，所述骨髓毒性导致所有造血谱系的累积耗竭（全血细胞减少），骨髓CNU敏感性可能是由于CNU诱导的DNA损伤修复效率低下所致;相对于其他组织，骨髓细胞表达极低水平的O-6-甲基鸟嘌呤DNA甲基转移酶（MGMT）蛋白，其修复细胞毒性O-6-氯乙基鸟嘌呤DNA损伤，使用一个简化的重组逆转录病毒载体表达人MGMT基因的磷酸甘油酸激酶启动子（PGK-MGMT）的控制下，我们增加了小鼠骨髓来源的细胞修复CNU诱导的DNA损伤的能力。用基因修饰的表达MGMT的造血干细胞稳定重建小鼠骨髓，对1，3-双（2-氯乙基）-1-亚硝基脲（BCNU）（一种常用于化疗的CNU）的细胞毒性作用具有相当大的抵抗力。从移植PGK-MGMT转导细胞的小鼠中收获的骨髓显示出广泛的体外BCNU抗性。此外，MGMT在小鼠骨髓中的表达赋予了体内对BCNU诱导的全血细胞减少症的抵抗力，并显着降低了由于骨髓发育不全而导致的BCNU诱导的死亡率。这些数据表明，原始造血干细胞中DNA烷基化修复的增加赋予多谱系保护免受BCNU的骨髓抑制作用，并提出了一种可能的方法来保护癌症患者免受CNU化疗相关的毒性。
The chloroethylnitrosourea (CNU) alkylating agents are commonly used for cancer chemotherapy, but their usefulness is limited by severe bone marrow toxicity that causes the cumulative depletion of all hematopoietic lineages (pancytopenia), Bone marrow CNU sensitivity is probably due to the inefficient repair of CNU-induced DNA damage; relative to other tissues, bone marrow cells express extremely Low levels of the O-6-methylguanine DNA methyltransferase (MGMT) protein that repairs cytotoxic O-6-chloroethylguanine DNA lesions, Using a simplified recombinant retroviral vector expressing the human MGMT gene under control of the phosphoglycerate kinase promoter (PGK-MGMT) we increased the capacity of murine hone marrow-derived cells to repair CNU-induced DNA damage. Stable reconstitution of mouse bone marrow with genetically modified, MGMT-expressing hematopoietic stem cells conferred considerable resistance to the cytotoxic effects of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), a CNU commonly used for chemotherapy. Bone marrow harvested from mice transplanted with PGK-MGMT-transduced cells showed extensive in vitro BCNU resistance. Moreover, MGMT expression in mouse bone marrow conferred in vivo resistance to BCNU-induced pancytopenia and significantly reduced BCNU-induced mortality due to bone marrow hypoplasia. These data demonstrate that increased DNA alkylation repair in primitive hematopoietic stem cells confers multilineage protection from the myelosuppressive effects of BCNU and suggest a possible approach to protecting cancer patients from CNU chemotherapy-related toxicity.