Dual Targeting of Tumor Angiogenesis and Chemotherapy by Endostatin-Cytosine Deaminase-Uracil Phosphoribosyltransferase

被引:22
作者
Chen, Chun-Te [1 ,4 ]
Yamaguchi, Hirohito [1 ]
Lee, Hong-Jen [1 ,4 ]
Du, Yi [1 ,4 ]
Lee, Heng-Huan [1 ,4 ]
Xia, Weiya [1 ]
Yu, Wen-Hsuan [1 ,4 ]
Hsu, Jennifer L. [1 ,5 ,6 ]
Yen, Chia-Jui [1 ]
Sun, Hui-Lung [1 ]
Wang, Yan [1 ]
Yeh, Edward T. H. [3 ]
Hortobagyi, Gabriel N. [2 ]
Hung, Mien-Chie [1 ,4 ,5 ,6 ]
机构
[1] Univ Texas Houston Hlth Sci Ctr, Dept Mol & Cellular Oncol, Houston, TX USA
[2] Univ Texas Houston Hlth Sci Ctr, Dept Breast Med Oncol, Houston, TX USA
[3] Univ Texas Houston Hlth Sci Ctr, Dept Cardiol, Houston, TX USA
[4] Univ Texas Houston Hlth Sci Ctr, Grad Sch Biomed Sci, Houston, TX USA
[5] China Med Univ & Hosp, Ctr Mol Med, Taichung, Taiwan
[6] China Med Univ & Hosp, Grad Inst Canc Biol, Taichung, Taiwan
关键词
RECOMBINANT HUMAN ENDOSTATIN; METASTATIC COLORECTAL-CANCER; I CLINICAL-TRIAL; STEM-LIKE CELLS; PHASE-II; BREAST-CANCER; FUSION GENE; MOLECULAR-MECHANISMS; GROWTH-FACTOR; THERAPY;
D O I
10.1158/1535-7163.MCT-10-1117
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
Several antiangiogenic drugs targeting VEGF/VEGF receptor (VEGFR) that were approved by the Food and Drug Administration for many cancer types, including colorectal and lung cancer, can effectively reduce tumor growth. However, targeting the VEGF signaling pathway will probably influence the normal function of endothelial cells in maintaining homeostasis and can cause unwanted adverse effects. Indeed, emerging experimental evidence suggests that VEGF-targeting therapy induced less tumor cell-specific cytotoxicity, allowing residual cells to become more resistant and eventually develop a more malignant phenotype. We report an antitumor therapeutic EndoCD fusion protein developed by linking endostatin (Endo) to cytosine deaminase and uracil phosphoribosyltransferase (CD). Specifically, Endo possesses tumor antiangiogenesis activity that targets tumor endothelial cells, followed by CD, which converts the nontoxic prodrug 5-fluorocytosine (5-FC) to the cytotoxic antitumor drug 5-fluorouracil (5-FU) in the local tumor area. Moreover, selective targeting of tumor sites allows an increasing local intratumoral concentration of 5-FU, thus providing high levels of cytotoxic activity. We showed that treatment with EndoCD plus 5-FC, compared with bevacizumab plus 5-FU treatment, significantly increased the 5-FU concentration around tumor sites and suppressed tumor growth and metastasis in human breast and colorectal orthotropic animal models. In addition, in contrast to treatment with bevacizumab/5-FU, EndoCD/5-FC did not induce cardiotoxicity leading to heart failure in mice after long-term treatment. Our results showed that, compared with currently used antiangiogenic drugs, EndoCD possesses potent anticancer activity with virtually no toxic effects and does not increase tumor invasion or metastasis. Together, these findings suggest that EndoCD/5-FC could become an alternative option for future antiangiogenesis therapy. Mol Cancer Ther; 10(8); 1327-36. (C) 2011 AACR.
引用
收藏
页码:1327 / 1336
页数:10
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