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Endostatin-Cytosine Deaminase Fusion Protein Suppresses Tumor Growth by Targeting Neovascular Endothelial Cells

Departments of ¹ Molecular and Cellular Oncology and ² Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center; ³ Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston; ⁴ Alchemgen Therapeutics, Inc., Houston, Texas

Requests for reprints: Mien-Chie Hung, Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Box 108, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-7477; Fax: 713-794-0209; E-mail: mhung{at}mdanderson.org.

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. (Cancer Res 2006; 66(1): 378-84)