Johansson M, Bergenheim A T, Henriksson R, Koskinen L O, Vallbo C, Widmark A
Department of Oncology, University Hospital, Umeå, Sweden.
Neurosurgery. 1997 Jul;41(1):237-43; discussion 243-4. doi: 10.1097/00006123-199707000-00038.
Estramustine (EaM) is a conjugate of nor-nitrogen mustard (NNM) and 17 beta-estradiol (E2) that has cytotoxic and radiosensitizing 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.
TBF was measured by radioactive microspheres, and tumor growth was measured by weight. Apoptosis was evaluated by in situ end labeling and gel electrophoresis. The effects of the constituents NNM and E2 were also evaluated.
EaM increased TBF to 153.8 ml/100 g/min 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 showed a tendency to increase cerebral blood flow. E2 increased TBF, whereas cerebral blood flow was unchanged. EaM resulted in a rapid reduction in tumor weight from 230 mg in untreated animals to 146 mg after 3 days of treatment. EaM induced an early transient fragmentation of deoxyribonucleic acid in glioma but not in the normal brain. Neither NNM nor E2 affected tumor weight.
EaM increases TBF in the BT4C rat glioma model with a concomitant rapid antitumoral effect. The increase in TBF could partially be induced by an estrogen-like action of EaM, but the rapid cytotoxic effect of the drug is obviously attributed to the intact EaM compound. This cytotoxic effect might be attributable to the induction of programmed cell death.
雌莫司汀（EaM）是去甲氮芥（NNM）与17β - 雌二醇（E2）的共轭物，对实验性恶性胶质瘤具有细胞毒性和放射增敏作用。其作用机制仅部分为人所知。为进一步在体内研究该机制，分析了其对肿瘤血流（TBF）和肿瘤生长的影响。
通过放射性微球测量TBF，通过称重测量肿瘤生长。通过原位末端标记和凝胶电泳评估细胞凋亡。还评估了NNM和E2成分的作用。
与未治疗对照组的94.0 ml/100 g/min相比，EaM治疗3天后TBF增加至153.8 ml/100 g/min，治疗10天后增加至153.9 ml/100 g/min。EaM治疗后脑血流未改变。NNM增加TBF，但也显示出增加脑血流的趋势。E2增加TBF，而脑血流未改变。EaM导致肿瘤重量从未治疗动物的230 mg迅速降至治疗3天后的146 mg。EaM诱导胶质瘤中脱氧核糖核酸早期短暂片段化，但在正常脑中未诱导。NNM和E2均未影响肿瘤重量。
在BT4C大鼠胶质瘤模型中，EaM增加TBF并伴有快速的抗肿瘤作用。TBF的增加可能部分由EaM类似雌激素的作用诱导，但该药物的快速细胞毒性作用显然归因于完整的EaM化合物。这种细胞毒性作用可能归因于程序性细胞死亡的诱导。
