Musser S M, Pan S S, Egorin M J, Kyle D J, Callery P S
Division of Developmental Therapeutics, University of Maryland Cancer Center, Baltimore 21201.
Chem Res Toxicol. 1992 Jan-Feb;5(1):95-9. doi: 10.1021/tx00025a016.
A reaction pathway by which thiotepa (N,N',N''-triethylenethiophosphoramide) and tepa (N,N',N''-triethylenethiophosphoramide), its major metabolite in humans, alkylate and depurinate DNA involves hydrolysis to aziridine (ethylene imine), a highly reactive monofunctional alkylating agent. Hydrolytic cleavage of an N-P bond of thiotepa releases aziridine which reacts with DNA, resulting in depurination and formation of the stable N-7 adduct 7-(2-aminoethyl)guanine and an aminoethyl adduct of adenine. Chromatographically identical alkylated products were observed in the reaction of thiotepa and tepa with individual nucleosides. Adducts with deoxycytidine or thymidine were not detected. Aziridine was measured by HPLC after derivatization with 1,2-naphthoquinone 4-sulfate. On the basis of the identity of the DNA adducts and the rate of formation of aziridine by hydrolysis in vitro, thiotepa is concluded to be a lipophilic, stabilized form of aziridine which serves as a cell-penetrating carrier of aziridine.
噻替派（N,N',N''-三乙烯硫代磷酰胺）及其在人体内的主要代谢产物替派（N,N',N''-三乙烯硫代磷酰胺）使DNA烷基化并脱嘌呤的反应途径涉及水解生成氮丙啶（乙烯亚胺），一种高反应性的单功能烷基化剂。噻替派的N-P键水解断裂释放出氮丙啶，其与DNA反应，导致脱嘌呤并形成稳定的N-7加合物7-(2-氨基乙基)鸟嘌呤和腺嘌呤的氨基乙基加合物。在噻替派和替派与单个核苷的反应中观察到色谱上相同的烷基化产物。未检测到与脱氧胞苷或胸苷的加合物。用1,2-萘醌-4-硫酸盐衍生化后，通过HPLC测定氮丙啶。基于DNA加合物的同一性以及体外水解生成氮丙啶的速率，得出结论：噻替派是氮丙啶的亲脂性稳定形式，可作为氮丙啶的细胞穿透载体。
