Hesdorffer C, Ayello J, Ward M, Kaubisch A, Vahdat L, Balmaceda C, Garrett T, Fetell M, Reiss R, Bank A, Antman K
Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
J Clin Oncol. 1998 Jan;16(1):165-72. doi: 10.1200/JCO.1998.16.1.165.
Normal bone marrow cells have little or no expression of the MDR p-glycoprotein product and, therefore, are particularly susceptible to killing by MDR-sensitive drugs, such as vinca alkaloids, anthracyclines, podophyllins, and paclitaxel and its congeners. Here we report the results of a phase I clinical trial that tested the safety and efficacy of transfer of the human multiple drug resistance (MDR1, MDR) gene into hematopoietic stem cells and progenitors in bone marrow as a means of providing resistance of these cells to the toxic effects of cancer chemotherapy.
Up to one third of the harvested cells of patients who were undergoing autologous bone marrow transplantation as part of a high-dose chemotherapy treatment for advanced cancer were transduced with an MDR cDNA-containing retrovirus; these transduced cells were reinfused together with unmanipulated cells after chemotherapy.
High-level MDR transduction of erythroid burst-forming unit (BFU-E) and colony-forming unit-granulocyte macrophage (CFU-GM) derived from transduced CD34+ cells was shown posttransduction and prereinfusion. However, only two of the five patients showed evidence of MDR transduction of their marrow at a low level at 10 weeks and 3 weeks, respectively, posttransplantation. The cytokine-stimulated transduced cells may be out-competed in repopulation by unmanipulated normal cells that are reinfused concomitantly. The MDR retroviral supernatant that was used was shown to be free of replication-competent retrovirus (RCR) before use, and all tests of patients' samples posttransplantation were negative for RCR. In addition, no adverse events with respect to marrow engraftment or other problems related to marrow transplantation were encountered.
These results indicate the feasibility and safety of bone marrow gene therapy with a potentially therapeutic gene, the MDR gene.
正常骨髓细胞几乎不表达或不表达多药耐药（MDR）P-糖蛋白产物，因此，它们对MDR敏感药物如长春花生物碱、蒽环类药物、鬼臼毒素以及紫杉醇及其同类物的杀伤作用尤为敏感。在此，我们报告一项I期临床试验的结果，该试验测试了将人类多药耐药（MDR1，MDR）基因导入骨髓造血干细胞和祖细胞的安全性和有效性，以此作为使这些细胞对癌症化疗毒性作用产生抗性的一种手段。
作为晚期癌症高剂量化疗治疗一部分而接受自体骨髓移植的患者，其收获细胞的多达三分之一用含MDR cDNA的逆转录病毒进行转导；化疗后，将这些转导细胞与未处理的细胞一起回输。
转导后及回输前，显示来自转导的CD34 +细胞的红系爆式集落形成单位（BFU-E）和粒-巨噬细胞集落形成单位（CFU-GM）有高水平的MDR转导。然而，五名患者中只有两名分别在移植后10周和3周显示其骨髓有低水平的MDR转导证据。细胞因子刺激的转导细胞在再增殖过程中可能会被同时回输的未处理正常细胞所取代。所用的MDR逆转录病毒上清液在使用前被证明无复制能力的逆转录病毒（RCR），移植后患者样本的所有检测RCR均为阴性。此外，未遇到与骨髓植入相关的不良事件或与骨髓移植相关的其他问题。
这些结果表明用具有潜在治疗作用的基因即MDR基因进行骨髓基因治疗的可行性和安全性。
