Retinoids induced t-PA synthesis by C6 glioma cells--role in tumoral haemorrhagic necrosis.
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.
Pernod
G
G
Laboratoire d'Hématologie, INSERM U 318, CHU de Grenoble, France.
Amalfitano
G
G
Le Magueresse
B
B
Berger
F
F
Polack
B
B
Kolodié
L
L
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000209:etiology; D003645:Death, Sudden / Q000209:etiology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005342:Fibrinolysis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D015474:Isotretinoin / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D009336:Necrosis; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D010959:Tissue Plasminogen Activator; D015474:Isotretinoin