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Inhibition of the Synthesis of Glycoproteins and Induction of the Differentiation of HL-60 Promyelocytic Leukemia Cells by 6-Methylmercaptopurine Ribonucleoside¹

Department of Pharmacology and Developmental Therapeutics Program, Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510

HL-60 promyelocytic leukemia cells were induced to differentiate along the granulocytic pathway by exposure to 6-methylmercaptopurine ribonucleoside (6-MMPR). The interference with cellular replication and the induction of terminal maturation by 6-MMPR appeared to be a cousequence of the inhibition of purine nucleotide biosynthesis de novo, since the simultaneous exposure of HL-60 cells to 6-MMPR and adenine completely prevented cellular differentiation, as measured by both nitroblue tetrazolium reduction and the phagocytosis of latex beads, and partially prevented growth inhibition.

The induction of HL-60 leukemia cell maturation by 6-MMPR was preceded by a marked reduction in the incorporation of [³H]mannose into glycoproteins and into the dolichol-oligosaccharide precursors of N-linked glycoprotein biosynthesis. Simultaneous exposure of HL-60 cells to 6-MMPR and adenine completely prevented the reduction in [³H]mannose incorporation into glycoproteins produced by the purine nucleoside antimetabolite. These findings suggest that the utilization of mannose for glycoprotein biosynthesis may be a component of the mechanism by which 6-MMPR causes the induction of the terminal differentiation of HL-60 leukemia cells.

¹ Supported in part by U.S. Public Health Service Grant CA-02817 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Pharmacology, Yale University School of Medicine, PO Box 3333, New Haven, CT 06510.

Received 4/27/87. Revised 8/27/87. Accepted 9/ 4/87.