Sensitivity of aldehyde dehydrogenases in murine tumor and hematopoietic progenitor cells to inhibition by chloral hydrate as determined by the ability of chloral hydrate to potentiate the cytotoxic action of mafosfamide.
Several murine aldehyde dehydrogenases, most notably AHD-2, are known to catalyze the detoxification of cyclophosphamide, mafosfamide, and other oxazaphosphorines. Thus, cellular sensitivity to these agents decreases as the relevant aldehyde dehydrogenase activity increases, and vice versa. Chloral hydrate is a sedative/hypnotic agent that is sometimes administered to patients being treated with cyclophosphamide. It is known to inhibit some, but not all, aldehyde dehydrogenases. Murine (CFU-S, CFU-GEMM and CFU-Mk) and human (CFU-Mix, CFU-GM, BFU-E and CFU-Mk) hematopoietic progenitor cells, as well as murine oxazaphosphorine-resistant (L1210/OAP and P388/CLA) tumor cells, are known to contain the relevant aldehyde dehydrogenase activity but the identity of the specific enzyme present in the normal cells is unknown and may be different than that, namely AHD-2, present in neoplastic cells. In that event, the potential exists to inhibit the detoxification of the oxazaphosphorines in tumor cells without inhibiting this event in normal cells; the net effect of such a selective inhibition would be to increase the margin of safety of the oxazaphosphorines. In ex vivo experiments, chloral hydrate markedly potentiated the antitumor activity of mafosfamide against oxazaphosphorine-resistant L1210/OAP and P388/CLA cells. It did not potentiate the cytotoxic action of mafosfamide against any of the murine or human hematopoietic cells tested, even at concentrations which fully restored the sensitivity of the resistant tumor cell lines to this agent. One explanation for these observations is that hematopoietic progenitor, and the resistant tumor, cells express different relevant aldehyde dehydrogenases and that these aldehyde dehydrogenases differ in their sensitivity to inhibition by chloral hydrate. Consistent with this notion were the observations that AHD-2 was exquisitely sensitive to inhibition by chloral hydrate, whereas two other aldehyde dehydrogenases that also catalyze the detoxification of aldophosphamide, namely AHD-12a, b and AHD-13, were relatively unaffected.
Maki
P A
PA
Department of Pharmacology, University of Minnesota, Minneapolis 55455.
Sladek
N E
NE
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D002460:Cell Line / Q000187:drug effects / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects; D002697:Chloral Hydrate / Q000494:pharmacology*; D003114:Colony-Forming Units Assay; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010752:Phosphoramide Mustards / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D010752:Phosphoramide Mustards; D002697:Chloral Hydrate; C048341:mafosfamide; C006446:aldophosphamide; D003520:Cyclophosphamide; D000444:Aldehyde Dehydrogenase