Targeted endostatin-cytosine deaminase fusion gene therapy plus 5-fluorocytosine suppresses ovarian tumor growth

被引：18
|
作者：
Sher, Y-P [1 ,3 ]
Chang, C-M [1 ]
Juo, C-G [5 ]
Chen, C-T [7 ]
Hsu, J. L. [7 ,8 ]
Lin, C-Y [2 ,3 ]
Han, Z. [7 ]
Shiah, S-G [6 ]
Hung, M-C [1 ,4 ,7 ,8 ]
机构：
[1] China Med Univ Hosp, Ctr Mol Med, Taichung, Taiwan
[2] China Med Univ Hosp, Div Hematol & Oncol, Taichung, Taiwan
[3] China Med Univ, Grad Inst Clin Med Sci, Taichung, Taiwan
[4] China Med Univ, Grad Inst Canc Biol, Taichung, Taiwan
[5] Chang Gung Univ, Mol Med Res Ctr, Tao Yuan, Taiwan
[6] Natl Hlth Res Inst, Natl Inst Canc Res, Miaoli, Taiwan
[7] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA
[8] Asia Univ, Taichung, Taiwan
来源：
ONCOGENE | 2013年 / 32卷 / 09期
关键词：
ovarian cancer; anti-angiogenesis; VISA; gene therapy; CANCER; EXPRESSION; SURVIVIN; DELIVERY; CELLS; YEAST; 5-FLUOROURACIL; ANGIOGENESIS; CHEMOTHERAPY; CISPLATIN;
D O I：
10.1038/onc.2012.134
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
There are currently no effective therapies for cancer patients with advanced ovarian cancer, therefore developing an efficient and safe strategy is urgent. To ensure cancer-specific targeting, efficient delivery, and efficacy, we developed an ovarian cancer-specific construct (Survivin-VISA-hEndoyCD) composed of the cancer specific promoter survivin in a transgene amplification vector (VISA; VP16-GAL4-WPRE integrated systemic amplifier) to express a secreted human endostatin-yeast cytosine deaminase fusion protein (hEndoyCD) for advanced ovarian cancer treatment. hEndoyCD contains an endostatin domain that has tumor-targeting ability for anti-angiogenesis and a cytosine deaminase domain that converts the prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic drug, 5-fluorouracil. Survivin-VISA-hEndoyCD was found to be highly specific, selectively express secreted hEndoyCD from ovarian cancer cells, and induce cancer-cell killing in vitro and in vivo in the presence of 5-FC without affecting normal cells. In addition, Survivin-VISA-hEndoyCD plus 5-FC showed strong synergistic effects in combination with cisplatin in ovarian cancer cell lines. Intraperitoneal (i.p.) treatment with Survivin-VISA-hEndoyCD coupled with liposome attenuated tumor growth and prolonged survival in mice bearing advanced ovarian tumors. Importantly, there was virtually no severe toxicity when hEndoyCD is expressed by Survivin-VISA plus 5-FC compared with CMV plus 5-FC. Thus, the current study demonstrates an effective cancer-targeted gene therapy that is worthy of development in clinical trials for treating advanced ovarian cancer. Oncogene (2013) 32, 1082-1090; doi:10.1038/onc.2012.134; published online 7 May 2012
引用
收藏
页码：1082 / 1090
页数：9
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