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Vol. 53, Issue 3, 422-428, March 1998
Medical Research Council Group in the Radiation Sciences,
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine,
Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada
Epipodophyllotoxin derivatives, such as etoposide (VP-16), constitute
an important class of anticancer agents, the major cytotoxic effects of
which are associated with trapping of the topoisomerase II/DNA
cleavable complex and formation of protein-DNA cross-links and nicked
DNA. VP-16, however, can be metabolized to several highly reactive
products, including an ortho-quinone (VPQ). The inhibitory activity of VPQ against purified human topoisomerase II
processing of supercoiled DNA was studied and compared with that of the
parent compound, VP-16. Our results show that VPQ is a powerful
inhibitor of topoisomerase II, which prevents DNA strand passage in the
presence of ATP. As with VP-16, trapping of the cleavable complex is
highly reversible upon removal of divalent ions, which indicating that
VPQ alters the cleavage-reunion equilibrium of topoisomerase II and DNA
mainly by noncovalent interactions, as does the parent compound.
However, we observed several differences between the effects induced by
VP-16 and VPQ, including a strong inhibition of the second DNA strand
religation, which implies the involvement of additional (asymmetric)
mode(s) of interactions of the VPQ, possibly by interference with ATP binding by the homodimeric enzyme, and/or involving covalent
interactions. Reduced or oxidized glutathione prevented trapping of the
topoisomerase/DNA cleavable complex by VPQ, but not by VP-16, probably
by forming covalent adducts with the former.
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