RETINOIDS INDUCE T-PA SYNTHESIS BY C6 GLIOMA-CELLS - ROLE IN TUMORAL HEMORRHAGIC NECROSIS

Treatment of rat C6 glioma with high doses of 13 cis-retinoic acid (cR A) was responsible for death related to haemorrhagic necrosis localize d to the tumor. Our aim was to explore this adverse effect of retinoid treatment, We show that cRA-treated C6 glioma at 25 mg/kg/day for 18 days exhibits in vivo an increased t-PA activity, which is responsible for a localized tumor fibrinolytic activity. Production of t-PA is su pported by specific enhancement of gene expression, as was shown by th e increase in t-PA mRNA (X 2.3). This production is a direct effect of cRA when treating the tumor, since tumor cells themself do not produc e enough t-PA and treatment of control rats does not increase the t-PA level. t-PA production by rat C6 glioma is in vivo related to the spe cific synthesis of t-PA by the C6 cell-line. The stimulation of C6 cel l-line by cRA in vitro is dose-dependent and reached a maximum for 3 a nd 3b mu M at the 72nd h. So cRA-treated C6 glioma cells produce t-PA which appears to be the major species associated with the fibrinolytic activity-induced intra-tumoral haemorrhage after exposure to retinoid treatment.