title: Targeted endostatin-cytosine deaminase fusion gene therapy plus 5-fluorocytosine suppresses ovarian tumor growth.
abstract: 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.
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Y-P
authors.initials: YP
authors.lastname: Sher
authors.forename: C-M
authors.initials: CM
authors.lastname: Chang
authors.forename: C-G
authors.initials: CG
authors.lastname: Juo
authors.forename: C-T
authors.initials: CT
authors.lastname: Chen
authors.forename: J L
authors.initials: JL
authors.lastname: Hsu
authors.forename: C-Y
authors.initials: CY
authors.lastname: Lin
authors.forename: Z
authors.initials: Z
authors.lastname: Han
authors.forename: S-G
authors.initials: SG
authors.lastname: Shiah
authors.forename: M-C
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D043525:Cytosine Deaminase / Q000235:genetics; D043169:Endostatins / Q000235:genetics; D005260:Female; D005437:Flucytosine / Q000627:therapeutic use*; D050939:Gene Fusion; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D043169:Endostatins; D011993:Recombinant Fusion Proteins; D005437:Flucytosine; D043525:Cytosine Deaminase