Kohn F R, Sladek N E
Biochem Pharmacol. 1985 Oct 1;34(19):3465-71. doi: 10.1016/0006-2952(85)90719-1.
The ex vivo sensitivity of murine pluripotent hematopoietic stem cells (CFU-S) and myeloid progenitor cells (CFU-GM) to 4-hydroperoxycyclophosphamide, ASTA Z 7557, phosphoramide mustard, acrolein, melphalan, and cis-platinum was determined in the absence and presence of known (disulfiram, diethyldithiocarbamate, cyanamide) or suspected [ethylphenyl(2-formylethyl)phosphinate] inhibitors of aldehyde dehydrogenase activity. As compared to CFU-GM, CFU-S were less sensitive to the oxazaphosphorine agents, 4-hydroperoxycyclophosphamide and ASTA Z 7557. The two cell populations were approximately equisensitive to acrolein as well as to the non-oxazaphosphorine cross-linking agents, phosphoramide mustard, melphalan and cis-platinum. All four inhibitors of aldehyde dehydrogenase activity potentiated the cytotoxic action of the oxazaphosphorines toward CFU-S; they did not potentiate the cytotoxic action of acrolein or the non-oxazaphosphorines toward these cells. The inhibitors did not potentiate the cytotoxic action of the oxazaphosphorines, non-oxazaphosphorines, or acrolein toward CFU-GM. Pyridoxal, a substrate for aldehyde oxidase, did not potentiate the cytotoxic action of oxazaphosphorines toward CFU-S. Cellular NAD-linked aldehyde dehydrogenases are known to catalyze the oxidation of the major transport form of cyclophosphamide, 4-hydroxycyclophosphamide/aldophosphamide, to an inactive metabolite, carboxyphosphamide. Our observations suggest that (1) aldehyde dehydrogenase activity is an important determinant of the sensitivity of a cell population to the oxazaphosphorines, (2) CFU-GM lack the relevant aldehyde dehydrogenase activity, and (3) the phenotypic basis for the relative insensitivity of CFU-S to oxazaphosphorines is the aldehyde dehydrogenase activity contained by these cells.
在不存在和存在已知的（双硫仑、二乙基二硫代氨基甲酸盐、氨基氰）或疑似的[乙基苯基(2-甲酰基乙基)次膦酸酯]醛脱氢酶活性抑制剂的情况下，测定了小鼠多能造血干细胞（CFU-S）和髓系祖细胞（CFU-GM）对4-氢过氧环磷酰胺、ASTA Z 7557、磷酰胺氮芥、丙烯醛、美法仑和顺铂的体外敏感性。与CFU-GM相比，CFU-S对恶唑磷类药物4-氢过氧环磷酰胺和ASTA Z 7557的敏感性较低。这两种细胞群体对丙烯醛以及对非恶唑磷类交联剂磷酰胺氮芥、美法仑和顺铂的敏感性大致相同。所有四种醛脱氢酶活性抑制剂均增强了恶唑磷类药物对CFU-S的细胞毒性作用；它们并未增强丙烯醛或非恶唑磷类药物对这些细胞的细胞毒性作用。这些抑制剂并未增强恶唑磷类药物、非恶唑磷类药物或丙烯醛对CFU-GM的细胞毒性作用。醛氧化酶的底物吡哆醛并未增强恶唑磷类药物对CFU-S的细胞毒性作用。已知细胞内与NAD相关的醛脱氢酶可催化环磷酰胺的主要转运形式4-羟基环磷酰胺/醛磷酰胺氧化为无活性代谢物羧基磷酰胺。我们的观察结果表明：（1）醛脱氢酶活性是细胞群体对恶唑磷类药物敏感性的重要决定因素；（2）CFU-GM缺乏相关的醛脱氢酶活性；（3）CFU-S对恶唑磷类药物相对不敏感的表型基础是这些细胞所含的醛脱氢酶活性。
