Unfulfilled promise of endostatin in a gene therapy-xenotransplant model of human acute lymphocytic leukemia
Unfulfilled promise of endostatin in a gene therapy-xenotransplant model of human acute lymphocytic leukemia
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DOI：
10.1006/mthe.2002.0573
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发表时间：
2002-04-01
影响因子：
12.4
通讯作者：
Eaves, C
中科院分区：
文献类型：
--
作者：
Eisterer, W;Jiang, XY;Eaves, C
逆转录病毒转导造血干细胞（HSC）为治疗骨髓恶性肿瘤提供了一个有吸引力的策略。因此，这种方法应该是感兴趣的抗血管生成剂对造血系统恶性肿瘤的生长与增强血管生成的治疗活性进行评估。多种研究表明内皮抑素是一种有效的体内外抗血管生成剂，并且可能对内皮抑素敏感的人类恶性肿瘤是人类B系急性淋巴细胞白血病（B-ALL）。所证明的人B-ALL细胞移植免疫缺陷小鼠骨髓的能力表明该系统用于使用共移植的非肥胖糖尿病-scid/scid（NOD/SCID）HSC测试内皮抑制素递送策略的潜力，所述HSC经工程改造以表达内皮抑制素。在这里，我们表明，尽管他们的突变scid基因，NOD/SCID造血干细胞可以转导内皮抑制素编码逆转录病毒的效率，导致在移植受体的内皮抑制素血清水平的几倍增加。然而，这并没有改变共同移植的人B-ALL母细胞的再生长。这些发现验证了这种基因转移方法，用于研究新疗法对移植NOD/SCID小鼠的原代人恶性细胞的影响，并质疑天然内皮抑制素在体内控制人B-ALL的效用。
Retroviral transduction of hematopoietic stem cells (HSCs) offers an attractive strategy for treating malignancies that home to the marrow. This approach should therefore be of interest for evaluating the therapeutic activity of anti-angiogenic agents on hematopoietic malignancies whose growth has been associated with enhanced angiogenesis. A variety of studies have indicated endostatin to be a potent anti-angiogenic agent both in vitro and in vivo, and a human malignancy that might be sensitive to endostatin is human B-lineage acute lymphoblastic leukemia (B-ALL). The demonstrated ability of human B-ALL cells to engraft the marrow of immunodeficient mice suggested the potential of this system for testing an endostatin delivery strategy using co-transplanted non-obese diabetic-scid/scid (NOD/SCID) HSCs engineered to express endostatin. Here we show that, in spite of their mutant scid gene, NOD/SCID HSCs can be transduced with an endostatin-encoding retrovirus at efficiencies that result in a several-fold increase in endostatin serum levels in transplanted recipients. However, this did not alter the regrowth of co-transplanted human B-ALL blasts. These findings validate this gene transfer approach for investigating effects of novel therapeutics on primary human malignant cells that engraft NOD/SCID mice and question the utility of native endostatin for controlling human B-ALL in vivo.