Eisenbrand G, Müller N, Schreiber J, Stahl W, Sterzel W, Berger M R, Zeller W J, Fiebig H
IARC Sci Publ. 1986(78):281-94.
Attempts to develop more effective and less toxic antineoplastic nitrosoureas are summarized. Previous research resulted in the synthesis and extensive preclinical testing of new, short-chain, water-soluble, but lipophilic compounds--1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)urea (HECNU) and 1-(2-chloroethyl)-1-nitroso-3-(methylene carboxamido)urea. Molecular mechanisms of reactions with biomolecules are discussed with regard to DNA alkylation and cross-linking, carbamoylation of glutathione and glutathione reductase inhibition. Results of a clinical phase-II study show that HECNU, as predicted from preclinical tests, exhibits outstanding activity in brain tumours. Future development concentrates on the use of carrier molecules for nitrosoureas. Results of an extensive structure-activity study with oestradiol-linked analogues show that an oestradiol-17 ester derivative is much more active than other analogues.
本文总结了开发更有效、毒性更低的抗肿瘤亚硝基脲的尝试。先前的研究导致了新型短链、水溶性但亲脂性化合物的合成和广泛的临床前测试——1-(2-氯乙基)-1-亚硝基-3-(2-羟乙基)脲（HECNU）和1-(2-氯乙基)-1-亚硝基-3-(亚甲基甲酰胺基)脲。讨论了与生物分子反应的分子机制，涉及DNA烷基化和交联、谷胱甘肽的氨甲酰化以及谷胱甘肽还原酶抑制。一项临床II期研究结果表明，如临床前测试所预测的，HECNU在脑肿瘤中表现出出色的活性。未来的发展集中在亚硝基脲载体分子的应用上。一项关于雌二醇连接类似物的广泛构效关系研究结果表明，一种雌二醇-17酯衍生物比其他类似物活性更高。
