Continuous intravascular secretion of endostatin in mice from transduced hematopoietic stem cells
Continuous intravascular secretion of endostatin in mice from transduced hematopoietic stem cells
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DOI：
10.1006/mthe.2002.0572
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发表时间：
2002-04-01
影响因子：
12.4
通讯作者：
Leboulch, P
中科院分区：
文献类型：
--
作者：
Pawliuk, R;Bachelot, T;Leboulch, P
内皮抑素是胶原XVIII的一个20 kda的羧基末端片段，是一类具有有效抗肿瘤活性的血管生成生生性抑制剂的主要成员。在小鼠中反复皮下注射重组内皮抑素，可使已建立的肿瘤永久消退至显微镜下的休眠状态，并促使人体临床试验的开始。然而，一个差异仍未解决：持续的肿瘤消退只观察到细菌产生的重组内皮抑素的不溶性沉淀形式。为了阐明这个问题，并建立一种可能克服蛋白质产生和传递障碍的癌症的全身抗血管生成基因治疗模型，我们用一种编码可分泌的内皮抑素的逆转录病毒转导小鼠造血干细胞。尽管所有移植小鼠的血管中都持续高水平分泌内皮抑素，但我们既没有检测到体内新生血管生成的抑制作用，也没有检测到抗肿瘤活性。解决这一矛盾可能来自目前正在进行的内皮抑素人体试验。
Endostatin, a 20-kDa carboxy-terminal fragment of collagen XVIII, is the leading member of a class of physiologic inhibitors of angiogenesis with potent antitumor activity. Repeated subcutaneous administration of recombinant endostatin in mice led to permanent regression of established tumors to a microscopic dormant state and prompted the initiation of human clinical trials. However, a discrepancy remained unresolved: sustained tumor regression has only been observed with a non-soluble, precipitated form of recombinant endostatin produced in bacteria. To shed light on this question and establish a model of systemic anti-angiogenic gene therapy of cancer that may surmount obstacles in protein production and delivery, we transduced murine hematopoietic stem cells with a retrovirus encoding a secretable form of endostatin. Despite continuous, high-level secretion of endostatin in the vasculature of all transplanted mice, we detected neither inhibition of in vivo neoangiogenesis nor antitumor activity. Resolution of this paradox may come from human trials of endostatin now underway.