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

We have determined the role of nitric oxide (NO)-mediated tumor cell killin g in the treatment of an animal model of murine ovarian carcinoma grown in the peritoneum with a combination of cisplatin and cationic liposomes conta ining an expression vector for interferon-gamma (IFN-gamma). The approach w as to determine whether the therapy was effective in mice homozygous for a disrupted inducible NO synthase (iNOS) allele; these mice were unable to pr oduce NO in response to IFN-gamma. iNOS (-/-) mice treated with both cispla tin and liposomal IFN-gamma gene did not produce a significant amount of NO in ascites (12.1 +/- 4.5 muM), although they expressed a: high level of IF N-gamma (9002 +/- 723 U/mL of ascitic fluid). As a result, mice died of tum ors within 11-62 days. However, wild-type mice treated with both cisplatin and liposomal IFN-gamma gene produced a significant amount of NO in ascites (113.7 +/- 17.9 muM) with a high level of IFN-gamma 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-gamma cytotoxi city.