Effect of aldehyde dehydrogenase inhibitors on the ex vivo sensitivity of human multipotent and committed hematopoietic progenitor cells and malignant blood cells to oxazaphosphorines.
Effect of aldehyde dehydrogenase inhibitors on the ex vivo sensitivity of human multipotent and committed hematopoietic progenitor cells and malignant blood cells to oxazaphosphorines.
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发表时间：
1987-06
期刊：
影响因子：
11.2
通讯作者：
F. Kohn;G. J. Landkamer;C. Manthey;N. Ramsay;N. Sládek
中科院分区：
文献类型：
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作者：
F. Kohn;G. J. Landkamer;C. Manthey;N. Ramsay;N. Sládek
在同时接触和不同时接触乙醛脱氢酶活性抑制剂的情况下，定量测定了人类多能和致力于造血祖细胞和几种培养的人类恶性血细胞系对“激活”的环磷酰胺类似物，即4-羟基过氧环磷酰胺和氨甲酰胺，以及对磷酰胺芥末的体外敏感性。乙醛脱氢酶活性抑制剂增强了4-羟基过氧环磷酰胺和马福胺对所有造血祖细胞的细胞毒作用，但不增强磷酰胺芥末对这些细胞的细胞毒作用。马福胺对培养的人类恶性血细胞的细胞毒作用的增强作用很小。分光光度分析显示，与正常小鼠肝脏或恶唑磷抗性L1210细胞相比，培养的人肿瘤细胞系中存在少量NAD连接的乙醛脱氢酶活性。已知细胞醛脱氢酶催化环磷酰胺生物活化的主要中间体4-羟基环磷酰胺/醛磷酰胺氧化成相对无毒的酸--羧基磷酰胺。因此，我们的发现表明，人多能造血祖细胞具有相应的乙醛脱氢酶活性，在分化为巨核细胞、粒/单核细胞和红系祖细胞时，相关活性保持不变，而在造血祖细胞向恶性细胞转化时，相关活性可能会丢失或减弱。
The ex vivo sensitivity of human multipotent and committed hematopoietic progenitor cells and several cultured human malignant blood cell lines to analogues of "activated" cyclophosphamide, namely, 4-hydroperoxycyclophosphamide and mafosfamide, and to phosphoramide mustard was quantified with and without concurrent exposure to an inhibitor of aldehyde dehydrogenase activity, namely, disulfiram, cyanamide, diethyldithiocarbamate, or ethylphenyl(2-formylethyl)phosphinate. Inhibitors of aldehyde dehydrogenase activity potentiated the cytotoxic action of 4-hydroperoxycyclophosphamide and mafosfamide toward all of the hematopoietic progenitors; they did not potentiate the cytotoxic action of phosphoramide mustard toward these cells. Potentiation of the cytotoxic action of mafosfamide toward cultured human malignant blood cells was minimal. Spectrophotometric assay revealed little NAD-linked aldehyde dehydrogenase activity present in the cultured human tumor cell lines as compared to that found in normal mouse liver or oxazaphosphorine-resistant L1210 cells. Cellular aldehyde dehydrogenases are known to catalyze the oxidation of 4-hydroxycyclophosphamide/aldophosphamide, the major intermediate in cyclophosphamide bioactivation, to the relatively nontoxic acid, carboxyphosphamide. Thus, our findings indicate that human multipotent hematopoietic progenitor cells contain the relevant aldehyde dehydrogenase activity, the relevant activity is retained upon differentiation to progenitors committed to the megakaryocytoid, granulocytoid/monocytoid, and erythroid lineages, and the relevant activity may be lost or diminished upon transformation of hematopoietic progenitors to malignant cells.