CYTOTOXIC EFFECT AND UPTAKE OF ESTRAMUSTINE IN A RAT GLIOMA MODEL

The cytotoxic effect of estramustine-phosphate (EMP) and the uptake in tumor tissue were investigated in a rat glioma model in vitro and in vivo. EMP, a combination of nornitrogen mustard and 17beta-estradiol, is a cytotoxic drug which main target is assumed to be the microtubule system. EMP and its metabolite estramustine (EaM) have a demonstrated anti-tumorous effect on human glioma cells in vitro. The drug uptake in tumor tissue and subsequently also the cytotoxic effect, is believe d to depend, at least partially, on a specific estramustine-binding pr otein (EMBP) which is present in human glioma tissue. In this study we have examined the effects and pharmacokinetics of EaM in the nitrosou rea induced BT4C rat glioma model. The tumor was characterized by infi ltrative growth with a histopathological picture resembling gliosarcom a. The presence of EMBP was demonstrated by immunohistology. In vitro EMP caused a dose-related inhibition of BT4C-cell growth. In vivo, in the rat model, a significant inhibition of tumor growth was obtained a fter administration of EaM 20 mg/kg/d i.p. The pharmacokinetics of EaM resembled that found in the human clinical situation with EaM as the main metabolite accumulating in tumor tissue. The mean concentration r atio of EaM was 15.6 in tumor versus serum, and 1.8 in tumor versus no rmal brain of 1.8. The cytotoxic effect demonstrated in the rat glioma model justifies further evaluation of EMP/EaM in the treatment of mal ignant gliomas.