Urinary metabolites of the antitumor agent cyclophosphamide.
Urinary metabolites of the antitumor agent cyclophosphamide.
复制标题
抗肿瘤剂环磷酰胺的尿液代谢物。
作者：
R. Struck;M. Kirk;L. Mellett;S. M. Dareer;D. L. Hill
2-N，N -双（2-氯乙基）磷酰二胺羧乙酯和4-酮环磷酰胺（2-[双（2-氯乙基）氨基]四氢-2 H-1，3，2-氧氮磷杂环戊烯-4-酮2-氧化物）已被分离和鉴定为用抗癌剂环磷酰胺（2-[双（2-氯乙基）氨基]四氢-2 H-1，3，2-氧氮磷杂环戊烯2-氧化物）处理的犬的尿液代谢产物。2-羧乙基N，N -双（2-氯乙基）二氨基磷酸酯是主要的尿液代谢产物，而4-酮基环磷酰胺是次要代谢产物，代表了环磷酰胺的第一个已知产物，保留了环结构。另一种尿代谢产物在水解时产生β-羟基丙酰胺，进一步表明环磷酰胺代谢中的主要氧化步骤发生在环的碳4上。这两种分离的代谢产物在体外对人表皮样癌细胞或体内对白血病L1210细胞均无高细胞毒性。这两种化合物都不在导致药物活性形式的途径上。
我们非常感谢D小姐。亚当森和M夫人。H.用于使用克隆细胞进行细胞毒性研究。Dr. L.威尔科夫和F博士。南方研究所化疗部的Schabel确定了在漩涡培养物中的细胞毒性试验，单层细胞和植入肿瘤细胞的小鼠。人尿取自M. D.安德森医院，休斯顿，通过医生詹姆斯吕斯的礼貌。Mr. T. C. Herren和H先生。E.芬奇分析了样本的放射性。微量分析和光谱测定由W. C.小科伯恩，和同事其中一些分析由Galbraith Laboratories（诺克斯维尔，田纳西州）进行。我很感激N博士。感谢布罗克最近赠送的一份合成4-酮环磷酰胺样品，并感谢A。Takamizawa对合成的2-羧乙基N，N -双（2-氯乙基）二氨基磷酸酯的样品进行了分析。
2-Carboxyethyl N, N -bis(2-chloroethyl)phosphorodiamidate and 4-ketocyclophosphamide (2-[bis(2-chloroethyl)amino]tetrahydro-2 H -1,3,2-oxazaphosphorin-4-one 2-oxide) have been isolated and identified as urinary metabolites of dogs treated with the anticancer agent cyclophosphamide (2-[bis(2-chloroethyl)amino]tetrahydro-2 H -1,3,2-oxazaphosphorine 2-oxide). 2-Carboxyethyl N, N -bis(2-chloroethyl)phosphorodiamidate is the major urinary metabolite, whereas 4-ketocyclophosphamide is a minor metabolite and represents the first known product of cyclophosphamide which retains the ring structure. Another urinary metabolite yields β-hydroxypropionamide on hydrolysis, a further indication that the primary oxidative step in the metabolism of cyclophosphamide occurs on carbon 4 of the ring. Neither of the two isolated metabolites is highly cytotoxic to human epidermoid cancer cells in vitro or to Leukemia L1210 cells in vivo . Neither compound is on a pathway leading to an active form of the drug.
ACKNOWLEDGMENTS We are very grateful to Miss D. Adamson and Mrs. M. H. Vail for performing the cytotoxicity studies with cloned cells. Dr. L. Wilkoff and Dr. F. Schabel of the Chemotherapy Department of Southern Research Institute determined the cytotoxicity tests in swirl cultures, with monolayers of cells, and with mice implanted with tumor cells. Human urine was obtained from patients at M. D. Anderson Hospital, Houston, through the courtesy of Dr. James Luce. Mr. T. C. Herren and Mr. H. E. Finch assayed samples for radioactivity. The microanalytical and spectral determinations were performed by Dr. W. C. Coburn, Jr., and associates. Some of the analyses were performed by Galbraith Laboratories, Knoxville, Tenn. We are indebted to Dr. N. Brock for a recent gift of a sample of synthetic 4-ketocyclophosphamide, and to Dr. A. Takamizawa for a sample of synthetic 2-carboxyethyl N,N -bis(2-chloroethyl)phosphorodiamidate.