Role for aldehyde dehydrogenase in survival of progenitors for murine blast cell colonies after treatment with 4-hydroperoxycyclophosphamide in vitro

Abstract

We have studied the effects of 4-hydroperoxycyclophosphamide (4-HC) on murine hemopoietic progenitors. We found dose-dependent killing and differential sensitivities of colony forming cells with burst forming units-erythrocyte being most sensitive and colony-forming units-granulocyte/erythrocyte/macrophage/megakaryocyte most resistant. We also tested the effects of 4-HC on more primitive murine progenitors which were identifiable in our assay system when the addition of interleukin-3 was delayed until Day 7. We found that the sensitivities of the progenitors for blast cell colonies are similar to those of colony-forming units-granulocyte/erythrocyte/macrophage/megakaryocyte and that late-appearing blast cell colonies were particularly resistant to 4-HC. In order to study the mechanism of differential sensitivities of murine progenitors to 4-HC, we examined the sensitivities of murine progenitors to 4-HC after brief incubation with diethylaminobenzaldehyde, an inhibitor of aldehyde dehydrogenase. Progenitors for granulocyte/macrophage colonies, granulocyte/erythrocyte/macrophage/megakaryocyte colonies, and blast cell colonies became more sensitive to 4-HC and the differential sensitivities of the progenitors disappeared following this treatment. We also tested the sensitivities of the progenitors to phenylketophosphamide, an analogue of 4-HC which is resistant to inactivation by aldehyde dehydrogenase. Various colony-forming units exhibited a similar dose response to this compound. These data indicate that intracellular levels of aldehyde dehydrogenase might play an important role in differential sensitivities of murine colony-forming units to 4-HC.