Therapy of Human Ovarian Cancer by Transfection with the Murine InterferonβGene: Role of Macrophage-Inducible Nitric Oxide Synthase

Abstract

The purpose of this study was to determine whether the local sustained production of murine interferon β (mIFN-β) could inhibit the growth of human ovarian cancer cells in the peritoneal cavity of nude mice. Human ovarian tumor Hey-A8 cells transfected with mIFN-β (Hey-β) or a control neomycin resistance vector (Hey-Neo) grew well in culture. Tumor cells were injected into the peritoneal cavity or under the subcutis of nuce mice. Parental (wild-type) or control transfected cells produced large tumors, whereas mIFN-β-transfected cells did not produce any tumors. The IFN-β-transfected cells prevented the outgrowth of bystander parental, control-transfected cells, and another human ovarian tumor cell line, SKOV3i.p.1, in the peritoneal cavity of nude mice. The IFN-β-transfected tumor cells stimulated a high level of nitric oxide (NO) production in murine macrophages under both in vitro and in vivo conditions, and only the NO-producing macrophages exhibited antitumor activity. Collectively, these results demonstrate that the local production of IFN-β can inhibit the in vivo growth of human ovarian cancer cells by upregulating the expression of the inducible nitric oxide synthase (iNOS) gene in host macrophages. In the present article we show that highly tumorigenic human ovarian carcinoma cells engineered to produce interferon β (IFN-β) fail to produce tumors in nude mice. The IFN-β-transfected cells stimulated the production of nitric oxide (NO) by murine macrophages, which directly correlated with suppression of tumorigenicity in bystander ovarian carcinoma cells.