Bertolini F, Corsini C, Lazzari L, Soligo D, De Monte L, Ward M, Bank A, Sirchia G
Centro Trasfusionale e di Immunologia dei Trapianti, Department of Hematology, Ospedale Maggiore Policlinico, Milano, Italy.
Leuk Lymphoma. 1996 Mar;21(1-2):17-23. doi: 10.3109/10428199609067574.
Autologous- or allogeneic-bone marrow transplantation are increasingly used to overcome the myelosuppressive effects of high dose chemotherapy administered to cancer patients. Transfer of the multidrug resistance (MDR) gene in hemopoietic progenitors has been proposed as a tool to administer higher and possibly more curative doses of chemotherapy. Murine models have demonstrated that retrovirus-mediated MDR transfer in bone marrow cells can render animals resistant to myeloablative doses of Taxol, and in vitro studies have shown that MDR-transduced human CD34+ cells can generate drug-resistant multipotential hemopoietic progenitors such as long term culture-initiating cells. Given these results, phase I clinical trials are currently under way to evaluate feasibility and treatment-related toxicity of MDR gene transfer in cancer patients by means of safe retroviral vectors. Finally, Taxol treatment of MDR transduced mice and human CD34+ cells have indicated that MDR is a dominant selectable marker in vitro and in vivo, and vectors carrying both MDR and non selectable genes such as beta-globin or glucocerebrosidase could be used in the next future for gene therapy of inherited disorders like thalassemia or Gaucher disease.
自体或异体骨髓移植越来越多地用于克服给予癌症患者的高剂量化疗的骨髓抑制作用。造血祖细胞中多药耐药（MDR）基因的转移已被提议作为一种给予更高剂量且可能更具治愈性的化疗药物的工具。小鼠模型已证明，逆转录病毒介导的骨髓细胞中MDR基因转移可使动物对大剂量紫杉醇产生抗性，并且体外研究表明，MDR转导的人CD34 +细胞可产生耐药的多能造血祖细胞，如长期培养起始细胞。鉴于这些结果，目前正在进行I期临床试验，以评估通过安全的逆转录病毒载体将MDR基因转移至癌症患者体内的可行性和与治疗相关的毒性。最后，对MDR转导的小鼠和人CD34 +细胞进行紫杉醇治疗表明，MDR在体外和体内都是显性选择标记，携带MDR和非选择基因（如β-珠蛋白或葡糖脑苷脂酶）的载体在不久的将来可用于治疗诸如地中海贫血或戈谢病等遗传性疾病的基因治疗。
