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Induction of Differentiation of Human Promyelocytic Leukemia Cells (HL60) by Metabolites of Hexamethylene Bisacetamide¹

Divisions of Developmental Therapeutics [S. W. S., M. J. E.] and Molecular Biology [A. W. H.], University of Maryland Cancer Center; Division of Medical Oncology, Department of Medicine, University of Maryland School of Medicine [M. J. E.]; and Department of Medicinal Chemistry/Pharmacognosy [L. A. G., P. S. C.], University of Maryland, School of Pharmacy, Baltimore, Maryland 21201

We studied the ability of five metabolites of hexamethylene bisacetamide (HMBA), which we had previously identified in patient urine, to induce differentiation or to influence differentiation induced by HMBA of a human promyelocytic cell line. Differentiation of HL60 cells was quantified by morphological changes and by the ability to reduce nitroblue tetrazolium. N-Acetyl-1,6-diaminohexane (NADAH), the deacetylated, first metabolite of HMBA, was a more potent inducer of HL60 differentiation than was HMBA. NADAH produced 20–30% differentiation at 0.25 mM and 30–40% differentiation at 0.5 mM. NADAH (1 mM) induced 2–3-fold more differentiation than did 1 mM HMBA. HL60 differentiation, induced by various combinations of HMBA and NADAH, reflected a combined effect of the two compounds. In contrast, 1,6-diaminohexane, at 0.5–5 mM, failed to induce HL60 differentiation. Similarly, 0.5–5 mM 6-acetamidohexanoic acid, the major metabolite of HMBA, and 6-aminohexanoic acid failed to induce differentiation of HL60 cells. However, 6-acetamidohexanoic acid, when combined with HMBA or NADAH at various concentrations and ratios, enhanced the differentiation of HL60 cells induced by these two compounds. This enhancement was most apparent with addition of 0.50–3.0 mM 6-acetamidohexanoic acid to HL60 cells incubated with 1.0–3.0 mM HMBA or 0.25–1.0 mM NADAH. 6-Aminohexanoic acid similarly enhanced HMBA-induced differentiation of HL60 cells. These in vitro results have implications in terms of the clinical application of HMBA and interpretation of the results of clinical trials performed to date and may provide some insight into the mechanism of HMBA-induced cellular differentiation.

¹ Supported in part by American Cancer Society Institutional Research Grant IN-174D, Maryland Cancer Program/University of Maryland, and Contract NO1-CM47734 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed.

Received 6/10/87. Revised 3/ 9/88. Accepted 3/30/88.