Eisenbrand G, Berger M R, Fischer J, Schneider M R, Tang W, Zeller W J
University of Kaiserslautern, Department of Food Chemistry and Environmental Toxicology, FRG.
Anticancer Drug Des. 1988 Mar;2(4):351-9.
2-Chloroethyl-N-nitrosoureas are highly active anti-neoplastic drugs in clinical use for many years. Therapy with these DNA cross-linking agents is limited by their toxic side effects, cumulative and delayed bone marrow toxicity being the main dose-limiting one. Since the intrinsic anti-tumour activity of the nitrosourea group is very high, coupling to appropriate carrier molecules represents a challenge for target-orientated chemotherapy. Many human tumours contain receptors for steroid hormones. Therefore, 2-chloroethyl-N-nitroso-carbamoyl(CNC)-amino acid derivatives have been developed that are linked to steroid hormones. In the series of oestradiol (E2)-linked analogues CNC-L-alanine-E2-17-ester was significantly superior to other E2-linked congeners and to the unlinked equimolar mixture when tested against hormone-dependent N-methyl-N-nitrosourea-induced mammary carcinoma of the rat. Relevance of E2 receptor contents for therapy with E2-linked drugs is evidenced by loss of superiority of this analogue in hormone-independent mammary carcinomas. Some androgen-linked CNC-amino acids showed substantial affinity to the androgen receptor and in part also to the progesterone receptor. A preliminary study in rat leukaemia L5222 revealed the CNC-L-alanine-dihydrotestosterone-17-ester to be highly active. Studies with hormone-dependent tumour models are under way.
2-氯乙基-N-亚硝基脲是临床应用多年的高效抗肿瘤药物。使用这些DNA交联剂进行治疗受到其毒副作用的限制，累积性和迟发性骨髓毒性是主要的剂量限制因素。由于亚硝基脲类的内在抗肿瘤活性非常高，与合适的载体分子偶联对靶向化疗来说是一项挑战。许多人类肿瘤含有甾体激素受体。因此，已开发出与甾体激素相连的2-氯乙基-N-亚硝基甲酰基（CNC）-氨基酸衍生物。在一系列与雌二醇（E2）相连的类似物中，当针对激素依赖性N-甲基-N-亚硝基脲诱导的大鼠乳腺癌进行测试时，CNC-L-丙氨酸-E2-17-酯明显优于其他与E2相连的同系物以及未相连的等摩尔混合物。在激素非依赖性乳腺癌中该类似物优势丧失，证明了E2受体含量与使用与E2相连药物治疗的相关性。一些与雄激素相连的CNC-氨基酸对雄激素受体显示出显著亲和力，部分还对孕激素受体有亲和力。对大鼠白血病L5222的初步研究表明，CNC-L-丙氨酸-二氢睾酮-17-酯具有高活性。针对激素依赖性肿瘤模型的研究正在进行中。
