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Role of Aldehyde Dehydrogenase in the Protection of Hematopoietic Progenitor Cells from 4-Hydroperoxycyclophosphamide by Interleukin 1ß and Tumor Necrosis Factor¹

Department of Medicine, Division of Medical Oncology, University of Florida, Gainesville, Florida 32610 [J. M., J. R. Z., Y. Z., M. A. G.], and Johns Hopkins Oncology Center, Baltimore, Maryland 21205 [M. O. C.]

Preincubation of human bone marrow cells with interleukin 1ß (IL-1) and tumor necrosis factor (TNF-) for 20 h can protect early progenitor cells from 4-hydroperoxycyclophosphamide (4-HC) toxicity. In this report, we have studied the mechanism for such protection. We examined the effect of the length of incubation time and found that preincubation for at least 20 h with IL-1 and TNF- is needed for significant protection. The addition of 2 µg/ml cycloheximide, a protein synthesis inhibitor, during the 20-h preincubation completely abolished the protection observed for all colony-forming cells. In order to study the role of aldehyde dehydrogenase (ALDH), an enzyme which inactivates 4-HC, we used diethylaminobenzaldehyde, an inhibitor of ALDH. Diethylaminobenzaldehyde was added during the last 10 min of the 20-h preincubation with IL-1 and TNF-. Diethylaminobenzaldehyde prevented the protection of colony-forming cells from 4-HC. Finally, using the same protection assay system, we showed that a 20-h preincubation with IL-1 and TNF- can also protect early progenitor cells from phenylketophosphamide, an analogue of 4-HC which is resistant to inactivation by ALDH. From these studies, we conclude that preincubation with IL-1 and TNF- for at least 20 h is required for the protection of early progenitor cells from 4-HC. During that time period, protein synthesis, specifically aldehyde dehydrogenase synthesis, is critical for the protection from 4-HC. Preincubation with IL-1 and TNF- also protects early progenitors from phenylketophosphamide. Because phenylketophosphamide cannot be metabolized by ALDH, the reason for this protection must be due to other, as yet unidentified, mechanisms.

¹ This work was supported by National Institutes of Health Grant AI 24709.

² To whom reprint requests should be addressed, at Department of Medicine, Box J-277, J. H. Miller Health Center, University of Florida, Gainesville, FL 32610.

Received 10/17/91. Accepted 1/23/92.

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