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

Cancer Gene Ther. 2000 Oct;7(10):1324-8. doi: 10.1038/sj.cgt.7700238.

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-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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects*
  • Ascites / immunology
  • Ascites / pathology
  • Chloramphenicol O-Acetyltransferase / biosynthesis
  • Cisplatin / therapeutic use*
  • Combined Modality Therapy
  • Female
  • Genetic Therapy / methods*
  • Interferon-gamma / genetics*
  • Liposomes
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide / metabolism*
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / therapy*
  • Plasmids
  • Recombinant Fusion Proteins / biosynthesis
  • Transfection
  • Tumor Cells, Cultured / drug effects*

Substances

  • Antineoplastic Agents
  • Liposomes
  • Recombinant Fusion Proteins
  • Nitric Oxide
  • Interferon-gamma
  • Chloramphenicol O-Acetyltransferase
  • Cisplatin