Ou-Yang Fu, Lan Keng-Li, Chen Chun-Te, Liu Jaw-Ching, Weng Chu-Li, Chou Chao-Kai, Xie Xiaoming, Hung Jen-Yu, Wei Yongkun, Hortobagyi Gabriel N, Hung Mien-Chie
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Cancer Res. 2006 Jan 1;66(1):378-84. doi: 10.1158/0008-5472.CAN-05-1578.
Endostatin, an angiogenesis inhibitor tested in multiple clinical trials, selectively targets neovascular endothelial cells, suppressing tumor growth. To enhance the therapeutic efficacy of endostatin, we fused endostatin with cytosine deaminase, which converts a prodrug 5-flucytosine into a cytotoxic 5-fluorouracil. This therapeutic strategy was developed based on the observation that the endostatin-green fluorescence protein gene and endostatin-luciferase gene selectively target to endothelial cells in vitro and to the tumor site in vivo, respectively. When we used the endostatin-cytosine deaminase fusion protein to treat s.c. grafted tumors or experimental metastasis tumors, our results showed that endostatin-cytosine deaminase treatment provided stronger tumor growth suppression and increased mean survival time of the mice compared with the treatments of endostatin alone, cytosine deaminase alone, or endostatin plus cytosine deaminase. The endostatin-cytosine deaminase protein significantly inhibited the growth of endothelial cells and preferentially induced tumor cell apoptosis. This endostatin-cytosine deaminase fusion approach opens an avenue for cancer-targeting therapy.
内皮抑素是一种在多项临床试验中进行过测试的血管生成抑制剂，它选择性地作用于新生血管内皮细胞，抑制肿瘤生长。为提高内皮抑素的治疗效果，我们将内皮抑素与胞嘧啶脱氨酶融合，胞嘧啶脱氨酶可将前药5-氟胞嘧啶转化为具有细胞毒性的5-氟尿嘧啶。这一治疗策略是基于以下观察结果开发的：内皮抑素-绿色荧光蛋白基因和内皮抑素-荧光素酶基因在体外分别选择性地作用于内皮细胞，在体内则选择性地作用于肿瘤部位。当我们使用内皮抑素-胞嘧啶脱氨酶融合蛋白治疗皮下移植瘤或实验性转移瘤时，结果显示，与单独使用内皮抑素、单独使用胞嘧啶脱氨酶或内皮抑素加胞嘧啶脱氨酶的治疗方法相比，内皮抑素-胞嘧啶脱氨酶治疗对肿瘤生长的抑制作用更强，并且延长了小鼠的平均存活时间。内皮抑素-胞嘧啶脱氨酶蛋白显著抑制内皮细胞的生长，并优先诱导肿瘤细胞凋亡。这种内皮抑素-胞嘧啶脱氨酶融合方法为癌症靶向治疗开辟了一条途径。
