Molecular Pharmacology, Vol 14, 442-447, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Preferential Inhibition of Terminal Deoxynucleotidyltransferase Activity among Deoxyribonucleic Acid Polymerase Activities of Leukemic and Normal Cells by Geldanamycin, Streptoval C, Streptovarone, and Dapmavarone

¹ Department of Experimental Therapeutics and Grace Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14263
² School of Chemical Sciences, University of lllinois, Urbana, Illinois 61801
³ Cancer Research, The Upjohn Company, Kalamazoo, Michigan 49001

Geldanamycin, streptoval C, streptovarone, and dapmavarone preferentially inhibited terminal deoxynucleotidyltransferase activity of Molt-4 cells and leukocytes from an acute lymphoblastic leukemia patient as compared with DNA polymerase , , and activities of these cells or of phytohemagglutinin-stimulated normal human lymphocytes. Streptovaricin C, the parent compound from which streptoval C, streptovarone, and dapmavarone are derived, was a poor inhibitor of these enzyme activities. Geldanamycin, streptoval C, and streptovarone inhibited terminal deoxynucleotidyltransferase activity more than reverse transcriptase activity of simian sarcoma virus, but dapmavarone inhibited these enzyme activities about the same. Inhibition of terminal deoxynucleotidyltransferase activity by these compounds was reversed by dilution but not by addition of extra initiator [(dA)_12-18], a divalent cation (Mn²⁺), bovine serum albumin, or substrate (dGTP). Prior incubation of each compound with the transferase resulted in greater inhibition than prior incubation with initiator or lack of prior incubation. These findings suggest that geldanamycin, streptoval C, streptovarone, and dapmavarone preferentially inhibit terminal deoxynucleotidyltransferase activity by reversibly binding to the enzyme and not to initiator or divalent cation.