SYSTEMIC EFFECTS OF CYTOKINES RELEASED BY GENE-TRANSDUCED TUMOR-CELLS- MARKED HYPERPLASIA INDUCED IN SMALL-BOWEL BY GAMMA-INTERFERON TRANSFECTANTS THROUGH HOST LYMPHOCYTES

Cells transduced with cytokine genes are currently used to enhance the anti-tumor and immunomodulatory effects of these molecules in cancer therapy. The sustained release of cytokine thus obtained can perturb m any homeostatic systems of the host. We have previously shown that the murine mammary adenocarcinoma TS/A transfected with the murine gamma- interferon (lFN-gamma) gene stimulates a strong immune response that i mpairs tumor growth. Mice bearing tiny tumors have serum IFN-gamma lev els constantly exceeding 100 IU/ml. Therefore, we asked which systemic effects can be triggered in mice by such transfectants. BALB/c mice b earing tumors produced by clone 16.6000 cells (which release 6,000 IU/ ml of IFN-gamma in culture) were compared to normal mice and to mice w ith tumors produced by parent cells transfected with the neomycin resi stance gene (NEO cells, no IFN-gamma release). Histological studies re vealed a marked hyperplasia of small bowel in mice bearing 16.6000 tum ors; the villi and crypts of these mice were >1.5 times longer than th ose of normal mice and of mice bearing NEO tumors. In vivo administrat ion of bromodeoxyuridine evidenced a 2.5-3 times increase in the proli ferative score of the intestinal crypts of mice bearing 16.6000 tumors compared to control mice. No intestinal alterations were observed in nude mice bearing 16.6000 tumors. T lymphocytes thus appear to play a causal role in this phenomenon. (C) 1995 Wiley-Liss, Inc.