Johansson M, Bergenheim A T, D'Argy R, Edman K, Gunnarsson P O, Widmark A, Henriksson R
Department of Oncology, Umeå University, Sweden.
Cancer Chemother Pharmacol. 1998;41(4):317-25. doi: 10.1007/s002800050745.
Estramustine (EaM), a carbamate ester of 17beta-estradiol and nor-nitrogen mustard, is a cytotoxic compound with antitumoral effect in malignant glioma in vitro and in vivo . However, knowledge of the pharmacokinetics of EaM in experimental glioma is limited. The objective of this study was therefore to investigate further the distribution of EaM in the BT4C rat glioma model. Assessment of EaM uptake and distribution was performed by quantitative whole-body autoradiography. In addition, the uptake of EaM and its metabolites estromustine (EoM), estradiol, and estrone were analyzed by gas chromatography. EaM was taken up from the circulation and was found to be the main product in glioma tissue. Whole-body autoradiography after [14C]-EaM administration revealed a strong 14C label simultaneously in tumor and normal brain tissue at 0.5 h after drug administration. In tumor tissue, sustained high levels of 14C label were detected at 12 h after drug administration. In contrast to the tumor, radioactivity in normal brain tissue rapidly leveled off, indicating a retention of radioactivity in the tumor. The tumor/brain radioactivity ratio reached a peak of 4.5 at 12 h after drug administration. High levels of 14C label were also found in pulmonary tissue. By gas chromatography, EoM was found to be the main metabolite in plasma. However, EaM reached higher levels in tumor tissue, with the mean tumor/plasma ratio being 11.7 as compared with 2.0 for EoM. Only low plasma levels of the estrogen metabolites were detected. In conclusion, EaM is taken up in the BT4C rat glioma tissue and is retained in the tumor as compared with normal brain tissue and plasma. EaM showed a greater selectivity for tumor tissue, exhibiting a high tumor/plasma ratio as compared with EoM. The distribution pattern after administration of EaM, as evaluated by both whole-body autoradiography and gas chromatography, supports the earlier suggestion that the uptake is related to a protein with EaM-binding characteristics.
雌莫司汀（EaM）是17β-雌二醇与去甲氮芥的氨基甲酸酯，是一种细胞毒性化合物，在体外和体内对恶性胶质瘤均有抗肿瘤作用。然而，关于EaM在实验性胶质瘤中的药代动力学知识有限。因此，本研究的目的是进一步研究EaM在BT4C大鼠胶质瘤模型中的分布情况。通过定量全身放射自显影评估EaM的摄取和分布。此外，通过气相色谱分析EaM及其代谢产物雌莫司汀（EoM）、雌二醇和雌酮的摄取情况。EaM从循环中被摄取，并且被发现是胶质瘤组织中的主要产物。给予[14C]-EaM后进行的全身放射自显影显示，给药后0.5小时，肿瘤组织和正常脑组织中同时出现强烈的14C标记。在给药后12小时，在肿瘤组织中检测到持续高水平的14C标记。与肿瘤不同，正常脑组织中的放射性迅速趋于平稳，表明放射性在肿瘤中有所保留。给药后12小时，肿瘤/脑放射性比值达到4.5的峰值。在肺组织中也发现了高水平的14C标记。通过气相色谱分析，发现EoM是血浆中的主要代谢产物。然而，EaM在肿瘤组织中达到更高水平，肿瘤/血浆平均比值为11.7，而EoM为2.0。仅检测到低水平的雌激素代谢产物。总之，与正常脑组织和血浆相比，EaM被摄取到BT4C大鼠胶质瘤组织中并保留在肿瘤中。与EoM相比，EaM对肿瘤组织表现出更大的选择性，呈现出高肿瘤/血浆比值。通过全身放射自显影和气相色谱评估，EaM给药后的分布模式支持了早期关于摄取与具有EaM结合特性的蛋白质相关的推测。
