Intraperitoneal gene therapy by rAAV provides long-term survival against epithelial ovarian cancer independently of survivin pathway.
Epithelial ovarian carcinoma is the leading cause of death from gynecological malignancies. Owing to the lack of an effective screening method, insidious onset, and non-specific symptoms, a majority of women present with advanced stage disease. Despite improvements from cytoreductive surgery and chemotherapy, recurrent disease remains a formidable challenge. In the present study, we demonstrate for the first time that stable intra-abdominal genetic transfer of endostatin and angiostatin (E+A) by recombinant adeno-associated virus (rAAV) provides sustained antitumor effects on the growth and dissemination of epithelial ovarian cancer in a mouse model. Further, when combined with paclitaxel (taxol), the effect of this therapy was dramatically increased and resulted in long-term tumor-free survival overcoming prior limitations of chemotherapy and gene therapy. The combined effects of angiosuppressive therapy and chemotherapy were found to be independently of survivin pathway. Evidence for the superior effects of the combination therapy was indicated by significantly lower ascites volume with less hemorrhage and tumor conglomerates, lower ascites vascular endothelial growth factor, higher tumor cell apoptosis and decreased blood vasculature, and long-term disease-free survival. Histopathology of visceral organs and liver enzyme assays indicated no toxicity or pathology.
Isayeva
T
T
Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA.
Ren
C
C
Ponnazhagan
S
S
D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000627:therapeutic use; D043168:Angiostatins / Q000235:genetics / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001202:Ascitic Fluid / Q000187:drug effects; D003131:Combined Modality Therapy; D000229:Dependovirus / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D043169:Endostatins / Q000235:genetics / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000378:metabolism / Q000633:toxicity; D051034:Inhibitor of Apoptosis Proteins; D007274:Injections, Intraperitoneal; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000401:mortality / Q000628:therapy*; D017239:Paclitaxel / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology; D015996:Survival Rate; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D043169:Endostatins; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D043168:Angiostatins; D017239:Paclitaxel