Pilot study of MDR1 gene transfer into hematopoietic stem cells and chemoprotection in metastatic breast cancer patients
Pilot study of MDR1 gene transfer into hematopoietic stem cells and chemoprotection in metastatic breast cancer patients
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DOI：
10.1111/j.1349-7006.2007.00571.x
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发表时间：
2007-10-01
期刊：
影响因子：
5.7
通讯作者：
Sugimoto, Yoshikazu
中科院分区：
文献类型：
--
作者：
Takahashi, Shunji;Aiba, Keisuke;Sugimoto, Yoshikazu
自体造血干细胞移植大剂量化疗的一个主要问题是重建骨髓功能不足，这限制了移植后化疗的效果。由于造血干细胞转导多药耐药1 （MDR1）基因可能会规避这一问题，我们进行了MDR1基因治疗转移性乳腺癌的初步研究。收集外周血干细胞，三分之一的细胞被MDR1逆转录病毒转导。在骨髓功能重建后，患者接受高剂量化疗，同时移植mdr1转导的和未处理的外周血干细胞。然后患者接受多西他赛化疗。2001年，两名患者接受了mdr1转导细胞的移植。移植后外周血mdr1转导的白细胞占总细胞数的3-5%，但逐渐减少。在多西紫杉醇化疗期间，观察到mdr1转导的白细胞率增加（高达10%）。两例患者多西他赛诱导的粒细胞减少的比较表明mdr1转导的细胞具有骨髓保护作用。未观察到严重副作用，患者完全缓解超过3年。mdr1转导细胞逐渐减少，到2004年底几乎完全消失。线性扩增介导的聚合酶链反应的结果显示，mdr1转导的白细胞没有异常扩增的迹象。第三名患者在2004年接受了mdr1转导细胞的移植。这些结果表明我们的MDR1基因治疗转移性乳腺癌的可行性，随访正在进行中。
A major problem in high-dose chemotherapy with autologous hematopoietic stem cell transplantation is insufficient function of reconstituted bone marrow that limits the efficacy of post-transplantation chemotherapy. Because transduction of hematopoietic stem cells with the multidrug resistance 1 (MDR1) gene might circumvent this problem, we conducted a pilot study of MDR1 gene therapy against metastatic breast cancer. Peripheral blood stem cells were harvested, and one-third of the cells were transduced with MDR1 retrovirus. After the reconstitution of bone marrow function, the patients received high-dose chemotherapy with transplantation of both MDR1-transduced and unprocessed peripheral blood stem cells. The patients then received docetaxel chemotherapy. Two patients received transplantation of the MDR1-transduced cells in 2001. Peripheral blood MDR1-transduced leukocytes were 3-5% of the total cells after transplantation, but decreased gradually. During docetaxel chemotherapy, an increase in the rate of MDR1-transduced leukocytes (up to 10%) was observed. Comparison of docetaxel-induced granulocytopenia in the two patients suggested a bone marrow-protective effect of the MDR1-transduced cells. No serious side-effect was observed, and the patients were in complete remission for more than 3 years. The MDR1-transduced cells gradually decreased and disappeared almost entirely by the end of 2004. Results of linear amplification-mediated polymerase chain reaction of the MDR1-transduced leukocytes suggested no sign of abnormal amplification of the transduced cells. A third patient received transplantation of the MDR1-transduced cells in 2004. These results suggest the feasibility of our MDR1 gene therapy against metastatic breast cancer, and follow-up is ongoing.