Endostatin-cytosine deaminase fusion protein suppresses tumor growth by targeting neovascular endothelial cells.
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.
Ou-Yang
Fu
F
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Lan
Keng-Li
KL
Chen
Chun-Te
CT
Liu
Jaw-Ching
JC
Weng
Chu-Li
CL
Chou
Chao-Kai
CK
Xie
Xiaoming
X
Hung
Jen-Yu
JY
Wei
Yongkun
Y
Hortobagyi
Gabriel N
GN
Hung
Mien-Chie
MC
D000230:Adenocarcinoma / Q000098:blood supply* / Q000235:genetics / Q000628:therapy; D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000628:therapy; D043525:Cytosine Deaminase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D043169:Endostatins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000235:genetics / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D043169:Endostatins; D011993:Recombinant Fusion Proteins; D043525:Cytosine Deaminase