Interferon-alpha gene therapy by lentiviral vectors contrasts ovarian cancer growth through angiogenesis inhibition.
Ovarian cancer represents a suitable disease for gene therapy because of the containment of neoplastic cells in the peritoneal cavity even at advanced tumor stages. The aim of this study was to investigate whether intraperitoneal administration of a lentiviral vector encoding murine interferon-alpha (LV-IFN) could have therapeutic activity in a transplantable ovarian cancer model. Multiple injections of low amounts of LV-IFN into severe combined immunodeficiency (SCID) mice bearing IGROV-1 or OC316 ovarian cancer cells elicited remarkable antitumor activity, leading to prolongation of survival in the majority of animals. A definitive cure was obtained in animals bearing PD-OVA#1 tumors, generated by injecting tumor cells isolated from the ascitic fluid of a patient into SCID mice. Interferon-alpha levels were detected in the peritoneal fluids but not in the serum of treated mice, indicating that production of the cytokine is mainly local, by both tumor and normal cells of the host. Antitumor effects were associated with a remarkable decrease in the formation of hemorrhagic ascites, an increase in ischemic tumor necrosis, and a reduction in microvessel density. In conclusion, our findings show that intracavitary IFN-alpha gene therapy, using a lentiviral vector, provides strong antitumor effects in murine models of ovarian cancer and reinforces the evidence that angiogenesis inhibition is a promising strategy for the treatment of localized tumors.
Indraccolo
Stefano
S
Department of Oncology and Surgical Sciences, University of Padua, Italy. stefano.indraccolo@unipd.it
Tisato
Veronica
V
Tosello
Valeria
V
Habeler
Walter
W
Esposito
Giovanni
G
Moserle
Lidia
L
Stievano
Laura
L
Persano
Luca
L
Chieco-Bianchi
Luigi
L
Amadori
Alberto
A
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007263:Infusions, Parenteral; D016898:Interferon-alpha / Q000008:administration & dosage / Q000235:genetics* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000662:veterinary; D013534:Survival
D000970:Antineoplastic Agents; D016898:Interferon-alpha