Effect of aldehyde dehydrogenase inhibitors on the ex vivo sensitivity of human multipotent and committed hematopoietic progenitor cells and malignant blood cells to oxazaphosphorines.
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.
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D003114:Colony-Forming Units Assay; D003484:Cyanamide / Q000494:pharmacology; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007939:Leukemia L1210 / Q000201:enzymology; D051379:Mice; D009243:NAD / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010721:Phosphinic Acids; D010752:Phosphoramide Mustards / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; D010752:Phosphoramide Mustards; D009243:NAD; C030090:phosphoramide mustard; C046656:(2-formylethyl)phenylphosphinic acid ethyl ester; D003484:Cyanamide; C048341:mafosfamide; D003520:Cyclophosphamide; D004050:Ditiocarb; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram; C011272:perfosfamide