Nitric oxide-mediated tumor cell killing of cisplatin-based interferon-γ gene therapy in murine ovarian carcinoma

Abstract

We have determined the role of nitric oxide (NO)-mediated tumor cell killing in the treatment of an animal model of murine ovarian carcinoma grown in the peritoneum with a combination of cisplatin and cationic liposomes containing an expression vector for interferon-γ (IFN-γ). The approach was to determine whether the therapy was effective in mice homozygous for a disrupted inducible NO synthase (iNOS) allele; these mice were unable to produce NO in response to IFN-γ. iNOS (−/−) mice treated with both cisplatin and liposomal IFN-γ gene did not produce a significant amount of NO in ascites (12.1 ± 4.5 μM), although they expressed a high level of IFN-γ (9002 ± 723 U/mL of ascitic fluid). As a result, mice died of tumors within 11–62 days. However, wild-type mice treated with both cisplatin and liposomal IFN-γ gene produced a significant amount of NO in ascites (113.7 ± 17.9 μM) with a high level of IFN-γ gene expression (9350 ± 1254 U/mL of ascitic fluid) and were free of tumors for at least 80 days. This result confirmed that NO was a direct mediator of IFN-γ cytotoxicity.