Pollok Karen E
Herman B Wells Center for Pediatric Research, The Riley Hospital for Children, 1044 West Walnut Street R4 427, Indianapolis, IN 46202, USA.
Curr Hematol Rep. 2003 Jul;2(4):341-7.
Strategies that confer chemoresistance to hematopoietic stem and progenitor cells have two important future applications in the treatment of cancer and genetic diseases. Because dose-intensification of many cancer chemotherapy protocols is limited by severe hematopoietic toxicities, generation of primitive hematopoietic cells resistant to DNA damage mediated by chemotherapy may protect patients from life-threatening blood cytopenias. In addition, in the context of genetic diseases, overexpression of a chemoresistance gene in stem and progenitor cells may allow for the enrichment of small numbers of transduced cells that would not possess an in vivo selective advantage. In this report, I discuss studies that use the DNA repair protein O6-methylguanine DNA methyltransferase to protect hematopoietic cells from alkylator therapy. I focus on investigations evaluating the ability of O6-methylguanine-DNA methyltransferase mutant proteins to confer heightened resistance to alkylator-mediated DNA damage in vivo.
赋予造血干细胞和祖细胞化学抗性的策略在癌症和遗传疾病治疗方面有两个重要的未来应用。由于许多癌症化疗方案的剂量强化受到严重造血毒性的限制，生成对化疗介导的DNA损伤具有抗性的原始造血细胞可能会保护患者免受危及生命的血细胞减少症的影响。此外，在遗传疾病的背景下，在干细胞和祖细胞中过表达化学抗性基因可能会使少量不具有体内选择优势的转导细胞得到富集。在本报告中，我讨论了利用DNA修复蛋白O6-甲基鸟嘌呤-DNA甲基转移酶保护造血细胞免受烷化剂治疗的研究。我重点关注评估O6-甲基鸟嘌呤-DNA甲基转移酶突变蛋白在体内赋予对烷化剂介导的DNA损伤更高抗性能力的研究。
