TUMOR BLOOD-FLOW AND THE CYTOTOXIC EFFECTS OF ESTRAMUSTINE AND ITS CONSTITUENTS IN A RAT GLIOMA MODEL

OBJECTIVE: Estramustine (EaM) is a conjugate of nor-nitrogen mustard ( NNM) and 17 beta-estradiol (E2) that has cytotoxic and radiosensitizin g effects on experimental malignant glioma. Its mechanism of action is only partly understood. To further investigate the mechanism in vivo, the effects on tumor blood flow (TBF) and tumor growth were analyzed. METHODS: TBF was measured by radioactive microspheres, and tumor grow th was measured by weight. Apoptosis was evaluated by in situ end labe ling and gel electrophoresis. The effects of the constituents NNM and E2 were also evaluated. RESULTS: EaM increased TBF to 153.8 ml/100 g/m in after 3 days and to 153.9 ml/100 g/min after 10 days of treatment, compared with 94.0 ml/100 g/min in untreated controls. Cerebral blood flow did not change after EaM treatment. NNM increased TBF but also sh owed a tendency to increase cerebral blood flow. E2 increased TBF, whe reas cerebral blood flow was unchanged. EaM resulted in a rapid reduct ion in tumor weight from 230 mg in untreated animals to 146 mg after 3 days of treatment. EaM induced an early transient fragmentation of de oxyribonucleic acid in glioma but not in the normal brain. Neither NNM nor E2 affected tumor weight. CONCLUSION: EaM increases TBF in the BT 4C rat glioma model with a concomitant rapid antitumoral effect. The i ncrease in TBF could partially be induced by an estrogen-like action o f EaM, but the rapid cytotoxic effect of the drug is obviously attribu ted to the intact EaM compound. This cytotoxic effect might be attribu table to the induction of programmed cell death.