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 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-gamma (IFN-gamma). 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-gamma. iNOS (-/-) mice treated with both cisplatin and liposomal IFN-gamma gene did not produce a significant amount of NO in ascites (12.1+/-4.5 microM), although they expressed a high level of IFN-gamma (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-gamma gene produced a significant amount of NO in ascites (113.7+/-17.9 microM) 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 cytotoxicity.
Son
K K
KK
Department of Pharmaceutics, Rutgers, The State University of New Jersey, College of Pharmacy, Piscataway 08854, USA. kson@rci.rutgers.edu
Hall
K J
KJ
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001201:Ascites / Q000276:immunology / Q000473:pathology; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D002945:Cisplatin / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D007371:Interferon-gamma / Q000235:genetics*; D008081:Liposomes; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010957:Plasmids; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000970:Antineoplastic Agents; D008081:Liposomes; D011993:Recombinant Fusion Proteins; D009569:Nitric Oxide; D007371:Interferon-gamma; D015500:Chloramphenicol O-Acetyltransferase; D002945:Cisplatin