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Induction of HL-60 Cell Differentiation by 3-Deaza-(±)-aristeromycin, an Inhibitor of S-Adenosylhomocysteine Hydrolase¹

Institute of Medical Biology, University of Tromsø, N-9001 Tromsø, Norway [J. A., P. S. P., A. B., L. S.], and Division of Biochemistry, Walter Reed Army Institute of Research, Washington DC, 20307-5100 [G. A. M., R. K. G., P. K. C.]

The metabolically stable inhibitor of S-adenosylhomocysteine hydrolase (AdoHcyase), 3-deaza-(±)-aristeromycin (dzAri) has recently been shown to induce differentiation in HL-60 cells. The present study was undertaken to characterize the cytostatic, cytotoxic, and differentiation inducing properties of dzAri in HL-60 cells and to investigate biochemical consequences of AdoHcyase inhibition. A dye exclusion test and a clonogenic assay were used to test cytotoxic and cytostatic properties. dzAri had reversible cytostatic effects on HL-60 cells at concentrations lower than 10 µM and partially reversible cytotoxic effects above 10 µM. The induction of differentiation was dependent upon concentration and time of exposure, with maximal effect after 6 days incubation with 5–10 µM dzAri. Washout experiments demonstrated that the cells were not committed to differentiation after 48 h of incubation with dzAri. The AdoHcyase of HL-60 cells was inhibited with a K_i of 20 nM. The concentration of S-adenosylhomocysteine increased dose dependently 48 h after incubation with 0.1–100 µM dzAri. The incorporation of [³H]methyl from [methyl-³H]methionine into 5-methylcytosine of DNA was reduced by 26% at 5 µM dzAri. The findings indicate that continuous presence of dzAri is necessary to induce differentiation and inhibit proliferation in HL-60 cells. The inhibition of AdoHcyase perturbs levels of transmethylation metabolites and the incorporation of [³H]methyl into 5-methylcytosine of DNA.

¹ This investigation was supported by grants from The Norwegian Cancer Society.

² To whom requests for reprints should be addressed.

Received 2/24/86. Revised 6/11/86. Accepted 7/29/86.

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