Blood, 1 August 2001, Vol. 98, No. 3, pp. 830-833
NEOPLASIA
Benzene metabolites antagonize etoposide-stabilized cleavable
complexes of DNA topoisomerase II
Ronda K. Baker,
Ebba U. Kurz,
David W. Pyatt,
Richard D. Irons, and
David J. Kroll
From Molecular Toxicology and Environmental Health
Sciences, School of Pharmacy, Cancer Center, Department of Preventative
Medicine, School of Medicine, and Department of Pathology, School of
Medicine, University of Colorado Health Sciences Center, Denver, CO.
Chronic exposure to benzene is associated with hematotoxicity and
acute myelogenous leukemia. Inhibition of topoisomerase II
(topo II)
has been implicated in the development of benzene-induced cytogenetic
aberrations. The purpose of this study was to determine the mechanism
of topo II inhibition by benzene metabolites. In a DNA
cleavage/relaxation assay, topo II was inhibited by
p-benzoquinone and hydroquinone at 10 µM and 10 mM,
respectively. On peroxidase activation, inhibition was seen with
4,4'-biphenol, hydroquinone, and catechol at 10 µM, 10 µM, and 30 µM, respectively. But, in no case was cleavable complex stabilization
observed and the metabolites appeared to act at an earlier step of the
enzyme cycle. In support of this conclusion, several metabolites
antagonized etoposide-stabilized cleavable complex formation and
inhibited topo II-DNA binding. It is therefore unlikely that
benzene-induced acute myelogenous leukemia stems from events invoked
for leukemogenic topo II cleavable complex-stabilizing antitumor agents.
