Cox P J, Phillips B J, Thomas P
Cancer Treat Rep. 1976 Apr;60(4):321-6.
The hypothesis that selective action of cyclophosphamide, compared to other nitrogen mustards, is due to a balance between enzymatic formation of inactive metabolites and chemical formation of the alkylating product was studied in view of previous observation in our laboratory. Metabolite analysis, inhibition of growth of tumor cells in culture, and kinetic analysis of relevant enzyme activities were used in this investigation. The effect of tissue-soluble enzyme fractions on biochemically prepared aldophosphamide, aldophosphamide analogs, and phosphoramide mustard showed: (a) a range of deactivation abilities with aldophosphamide (liver greater than kidney greater than intestinal mucosa greater than tumor greater than spleen = bovine serum albumin solution); (b) the formation of different amounts of carboxyphosphamide from aldophosphamide; and (c) only comparatively small reductions in the toxicity of phosphoramide mustard and of 4-hydroxy-4methylcyclophosphamide. Correlations were found between NAD+-dependent aldehyde dehydrogenase activity and the deactivation ability of tissue-soluble enzyme fractions. Blockage (by C4 substitution) or inhibition (by disulfiram) of secondary oxidation of aldophosphamide, mediated by aldehyde dehydrogenase, resulted in diminished deactivation ability in vitro and reduced selectivity in vivo.
鉴于我们实验室之前的观察结果，对环磷酰胺与其他氮芥相比具有选择性作用的假说进行了研究，该假说认为其选择性作用归因于无活性代谢产物的酶促形成与烷基化产物的化学形成之间的平衡。本研究采用代谢物分析、培养肿瘤细胞生长抑制以及相关酶活性的动力学分析方法。组织可溶性酶组分对生化制备的醛磷酰胺、醛磷酰胺类似物和磷酰胺氮芥的作用表明：(a) 醛磷酰胺失活能力的范围（肝脏＞肾脏＞肠黏膜＞肿瘤＞脾脏 = 牛血清白蛋白溶液）；(b) 醛磷酰胺形成不同量的羧基磷酰胺；(c) 磷酰胺氮芥和4-羟基-4-甲基环磷酰胺的毒性仅相对小幅降低。发现NAD⁺依赖性醛脱氢酶活性与组织可溶性酶组分的失活能力之间存在相关性。由醛脱氢酶介导的醛磷酰胺二次氧化的阻断（通过C4取代）或抑制（通过双硫仑）导致体外失活能力降低和体内选择性降低。
