Therapy of human ovarian cancer by transfection with the murine interferon beta gene: role of macrophage-inducible nitric oxide synthase.

The purpose of this study was to determine whether the local sustained production of murine interferon beta (mIFN-beta) 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-beta (Hey-beta) 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-beta-transfected cells did not produce any tumors. The IFN-beta-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-beta-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-beta 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.