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The Journal of Immunology, Vol 146, Issue 6 2052-2058, Copyright © 1991 by American Association of Immunologists

ARTICLES

Inhibitors of ADP-ribose polymerase decrease the resistance of HER2/neu- expressing cancer cells to the cytotoxic effects of tumor necrosis factor

A Lichtenstein, JF Gera, J Andrews, J Berenson and CF Ware
Department of Medicine, V.A. Wadsworth-UCLA Medical Center.

Four human ovarian and breast tumor lines expressing the HER2/neu oncogene were resistant to the cytotoxic and DNA-degradative activity of TNF. The resistance was not associated with altered TNF receptor function because Scatchard analysis of 125I-rTNF binding to HER2/neu- expressing target cells revealed receptors with normal binding parameters. Furthermore, the TNF receptors on the resistant lines were capable of signal transduction as evidence by the induction of ADP- ribose polymerase activity and MHC expression. TNF resistance was not reversed by coincubation with drugs that interrupted the glutathione redox cycle. In addition, although coincubation of HER2/neu-expressing targets with cycloheximide resulted in significant TNF-induced lysis, when compared to HER2/neu-nonexpressing targets similarly treated with cycloheximide, a significant relative resistance was still present. To investigate the role of ADP-ribosylation in the resistance of these targets, we used nontoxic concentrations of two inhibitors of ADP- ribose polymerase, 3-aminobenzamide, and nicotinamide. Both inhibitors completely reversed the resistance of HER2/neu-expressing targets to TNF-mediated cytotoxicity and DNA injury in a concentration-dependent fashion. These inhibitors of ADP-ribose polymerase did not act by down- regulating expression of HER2/neu oncogenes. In contrast, aminobenzamide and nicotinamide significantly diminished TNF-induced cytotoxicity of L929 targets. These data suggest that the activity of ADP-ribose polymerase may play a pivotal role in determining the fate of the target cell during exposure to TNF.


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 Molecular Cancer TherapeuticsHome page
M.-A. Lyu and M. G. Rosenblum
The immunocytokine scFv23/TNF sensitizes HER-2/neu-overexpressing SKBR-3 cells to tumor necrosis factor (TNF) via up-regulation of TNF receptor-1
Mol. Cancer Ther., August 1, 2005; 4(8): 1205 - 1213.
[Abstract] [Full Text] [PDF]


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