isotretinoin and Cerebral-Hemorrhage

Treatment of rat C6 glioma with high doses of 13 cis-retinoic acid (cRA) was responsible for death related to haemorrhagic necrosis localized 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 increase T-PA activity, which is responsible for a localized tumor fibrinolytic activity. Production of t-PA is supported by specific enhancement of gene expression, as was shown by the increase in t-PA mRNA (x 2.3). This production is a direct effect of cRA when treating the tumor, since tumor cells themselves do not produce 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 specific synthesis of t-PA by the C6 cell-line. The stimulation of C6 cell-line by cRA in vitro is dose-dependent and reached a maximum for 3 and 30 microM 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.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cerebral Hemorrhage; Death, Sudden; Drug Screening Assays, Antitumor; Female; Fibrinolysis; Gene Expression Regulation, Neoplastic; Glioma; Isotretinoin; Necrosis; Neoplasm Proteins; Neoplasm Transplantation; Rats; Rats, Sprague-Dawley; RNA, Messenger; RNA, Neoplasm; Tissue Plasminogen Activator; Tumor Cells, Cultured