Effects of aldehyde dehydrogenase inhibitors on the ex vivo sensitivity of murine late spleen colony-forming cells (day-12 CFU-S) and hematopoietic repopulating cells to mafosfamide (ASTA Z 7557).
The effects of inhibitors of aldehyde dehydrogenase activity on the sensitivity of murine pluripotent hematopoietic stem cells to oxazaphosphorine anticancer agents, e.g. mafosfamide, were examined using two different assay procedures. In the first part of the investigation, the ex vivo sensitivity of murine day-12 spleen colony-forming cells (CFU-S) to mafosfamide was determined in the absence and presence of known inhibitors of aldehyde dehydrogenase activity, viz. diethyldithiocarbamate and cyanamide. These results were compared to those generated for day-8 CFU-S. Day-12 CFU-S were less sensitive to mafosfamide, and to phosphoramide mustard, although the difference in sensitivity to the latter was less marked. Diethyldithiocarbamate and cyanamide each potentiated the cytotoxic action of mafosfamide toward both day-12 and day-8 CFU-S; they did not potentiate the cytotoxic action of phosphoramide mustard toward these cells. Since cellular aldehyde dehydrogenases are known to catalyze the oxidation of 4-hydroxycyclophosphamide/aldophosphamide, the major transport form of mafosfamide, to the relatively nontoxic acid, carboxyphosphamide, the results suggest that intracellular aldehyde dehydrogenase activity is a determinant of the sensitivity of day-12 CFU-S, as well as of day-8 CFU-S, to mafosfamide and other oxazaphosphorines, e.g. cyclophosphamide. In the second part of this investigation, a murine syngeneic bone marrow transplantation model was used to determine the ex vivo sensitivity of murine hematopoietic repopulating cells to mafosfamide in the absence and presence of diethyldithiocarbamate. Specifically, the ability of treated marrow grafts to repopulate the hematopoietic system, and thereby save recipients from the otherwise lethal effect of total body irradiation, was determined. Diethyldithiocarbamate potentiated the cytotoxic action of mafosfamide, but not that of phosphoramide mustard, toward hematopoietic repopulating cells. These observations support our previous contention that aldehyde dehydrogenase activity is an operative determinant with regard to the sensitivity of murine pluripotent hematopoietic stem cells to oxazaphosphorines.
Kohn
F R
FR
Sladek
N E
NE
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D016026:Bone Marrow Transplantation; D003114:Colony-Forming Units Assay; D003484:Cyanamide / Q000494:pharmacology; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects; D004357:Drug Synergism; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D008658:Inactivation, Metabolic / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D010752:Phosphoramide Mustards / Q000494:pharmacology*; D011828:Radiation Chimera; D013154:Spleen / Q000166:cytology; D013997:Time Factors
D010752:Phosphoramide Mustards; C030090:phosphoramide mustard; D003484:Cyanamide; C048341:mafosfamide; D003520:Cyclophosphamide; D004050:Ditiocarb; D000444:Aldehyde Dehydrogenase