LOCAL PRODUCTION OF TGF-BETA-1 INHIBITS CEREBRAL EDEMA, ENHANCES TNF-ALPHA INDUCED APOPTOSIS AND IMPROVES SURVIVAL IN A MURINE GLIOMA MODEL

We have previously reported that local secretion of either TNF-alpha o r TGF beta 1 by intracerebral SMA-560 malignant glioma tumor cells can reduce or eliminate tumor growth in mice. However, the use of TNF-alp ha, while improving the overall survival of tumor bearing animals, was associated with early toxic deaths due to cerebral edema. In the pres ent study, we demonstrate that TNF-alpha induces apoptosis of the SMA 560 cell Line, as does TGF beta 1, and that these two cytokines act in an additive fashion to enhance apoptosis and thus, to inhibit SMA 560 cell growth in vitro. Next, we show that the production of TGF beta 1 when added to TNF-alpha production by central nervous system tumors i n vivo abrogates any early deaths seen due to TNF-alpha toxicity and l eads to a larger percentage of animals surviving CNS tumor challenge. Finally, we demonstrate that the production of TGF beta 1 by tumor cel ls is associated with the abolition of tumor-associated cerebral edema in both TNF-alpha and in non-TNF-alpha producing tumors. These result s are important for the development of effective and less toxic therap ies for brain tumors, as well as for examining the pathogenesis of tum or-related cerebral edema. (C) 1998 Elsevier Science B.V. All rights r eserved.