ABROGATION OF TUMORIGENICITY AND METASTASIS OF MURINE AND HUMAN TUMOR-CELLS BY TRANSFECTION WITH THE MURINE IFN-BETA GENE - POSSIBLE ROLE OF NITRIC-OXIDE

The purpose of this study was to determine whether sustained local pro duction of murine IFN-beta (mIFN-beta) could inhibit the tumorigenicit y and metastasis of human and murine tumor cells implanted into nude m ice. Human melanoma cells (A375SM), renal carcinoma cells (SN12PM6), a nd colon carcinoma cells (KM12SM) were transfected with mIFN-beta or a control neomycin resistance vector. All cell lines grew well in cultu re. Tumor cells were injected into the subcutis, kidney, spleen, or la teral tail vein of nude mice. Parental or control transfected cells pr oduced local tumors and experimental or spontaneous lung metastases, w hereas mIFN-beta-transfected cells did not. In vivo survival experimen ts using [I-125]IdUdR-labeled cells showed that by day 7 after s.c. im plantation, all IFN-beta-transfected cells died. IFN-beta transfection prevented the outgrowth of parental or control-transfected cells only when they were injected together with transfected cells into one site , suggesting that IFN-beta promoted a local lysis of the bystander cel ls. Similar indirect antitumor activity was demonstrated in various hu man (KM12SM and SN12PM6) and murine (CT-26 colon carcinoma, RENCA rena l cell carcinoma, and 3LL Lewis lung carcinoma) tumors. The IFN-beta-t ransfected tumor cells stimulated a high level of nitric oxide product ion by murine macrophages under in vitro and in vivo conditions, which correlated with the vigorous nonspecific antitumor activity. Collecti vely, these results demonstrate that local production of IFN-beta can eradicate tumor cells of different histology by inducing inducible nit ric oxide synthase expression in infiltrating cells.