Aldehyde dehydrogenase activity as the basis for the relative insensitivity of murine pluripotent hematopoietic stem cells to oxazaphosphorines.
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.
D000171:Acrolein / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells; D002945:Cisplatin / Q000494:pharmacology; D003114:Colony-Forming Units Assay; D003484:Cyanamide / Q000494:pharmacology; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology; D004357:Drug Synergism; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010721:Phosphinic Acids; D010752:Phosphoramide Mustards / Q000494:pharmacology
D009588:Nitrogen Mustard Compounds; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; D010752:Phosphoramide Mustards; C030090:phosphoramide mustard; C046656:(2-formylethyl)phenylphosphinic acid ethyl ester; D003484:Cyanamide; D000171:Acrolein; C037933:Asta Z 7557; D003520:Cyclophosphamide; D004050:Ditiocarb; D000444:Aldehyde Dehydrogenase; D002945:Cisplatin; D008558:Melphalan; D004221:Disulfiram; C011272:perfosfamide