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Title: Ketoconazole attenuates radiation-induction of tumor necrosis factor

Abstract

Previous work has demonstrated that inhibitors of phospholipase A2 attenuate ionizing radiation-induced arachidonic acid production, protein kinase C activation, and prevent subsequent induction of the tumor necrosis factor gene. Because arachidonic acid contributes to radiation-induced tumor necrosis factor expression, the authors analyzed the effects of agents which alter arachidonate metabolism on the regulation of this gene. Phospholipase A2 inhibitors quinicrine, bromphenyl bromide, and pentoxyfylline or the inhibitor of lipoxygenase (ketoconazole) or the inhibitor of cycloxygenase (indomethacine) were added to cell culture 1 h prior to irradiation. Radiation-induced tumor necrosis factor gene expression was attenuated by each of the phospholipase A2 inhibitors (quinicrine, bromphenylbromide, and pentoxyfylline). Furthermore, ketoconazole attenuated X ray induced tumor necrosis factor gene expression. Conversely, indomethacin enhanced tumor necrosis factor expression following irradiation. The finding that radiation-induced tumor necrosis factor gene expression was attenuated by ketoconazole suggests that the lipoxygenase pathway participates in signal transduction preceding tumor necrosis factor induction. Enhancement of tumor necrosis factor expression by indomethacin following irradiation suggests that prostaglandins produced by cyclooxygenase act as negative regulators of tumor necrosis factor expression. Inhibitors of tumor necrosis factor induction ameliorate acute and subacute sequelae of radiotherapy. The authors propose therefore, that ketoconazole may reduce acute radiationmore » sequelae such as mucositis and esophagitis through a reduction in tumor necrosis factor induction or inhibition of phospholipase A2 in addition to its antifungal activity. 25 refs., 2 figs.« less

Authors:
; ; ;  [1]
  1. Dana Farber Cancer Institute, Boston, MA (United States)
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
86487
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 29; Journal Issue: 4; Other Information: PBD: 1 Jul 1994
Country of Publication:
United States
Language:
English
Subject:
56 BIOLOGY AND MEDICINE, APPLIED STUDIES; LYMPHOKINES; GENE REGULATION; OXYGENASES; RADIOSENSITIVITY; BIOLOGICAL RADIATION EFFECTS

Citation Formats

Hallahan, D E, Virudachalam, S, Kufe, D W, and Weichselbaum, R R. Ketoconazole attenuates radiation-induction of tumor necrosis factor. United States: N. p., 1994. Web. doi:10.1016/0360-3016(94)90566-5.
Hallahan, D E, Virudachalam, S, Kufe, D W, & Weichselbaum, R R. Ketoconazole attenuates radiation-induction of tumor necrosis factor. United States. https://doi.org/10.1016/0360-3016(94)90566-5
Hallahan, D E, Virudachalam, S, Kufe, D W, and Weichselbaum, R R. 1994. "Ketoconazole attenuates radiation-induction of tumor necrosis factor". United States. https://doi.org/10.1016/0360-3016(94)90566-5.
@article{osti_86487,
title = {Ketoconazole attenuates radiation-induction of tumor necrosis factor},
author = {Hallahan, D E and Virudachalam, S and Kufe, D W and Weichselbaum, R R},
abstractNote = {Previous work has demonstrated that inhibitors of phospholipase A2 attenuate ionizing radiation-induced arachidonic acid production, protein kinase C activation, and prevent subsequent induction of the tumor necrosis factor gene. Because arachidonic acid contributes to radiation-induced tumor necrosis factor expression, the authors analyzed the effects of agents which alter arachidonate metabolism on the regulation of this gene. Phospholipase A2 inhibitors quinicrine, bromphenyl bromide, and pentoxyfylline or the inhibitor of lipoxygenase (ketoconazole) or the inhibitor of cycloxygenase (indomethacine) were added to cell culture 1 h prior to irradiation. Radiation-induced tumor necrosis factor gene expression was attenuated by each of the phospholipase A2 inhibitors (quinicrine, bromphenylbromide, and pentoxyfylline). Furthermore, ketoconazole attenuated X ray induced tumor necrosis factor gene expression. Conversely, indomethacin enhanced tumor necrosis factor expression following irradiation. The finding that radiation-induced tumor necrosis factor gene expression was attenuated by ketoconazole suggests that the lipoxygenase pathway participates in signal transduction preceding tumor necrosis factor induction. Enhancement of tumor necrosis factor expression by indomethacin following irradiation suggests that prostaglandins produced by cyclooxygenase act as negative regulators of tumor necrosis factor expression. Inhibitors of tumor necrosis factor induction ameliorate acute and subacute sequelae of radiotherapy. The authors propose therefore, that ketoconazole may reduce acute radiation sequelae such as mucositis and esophagitis through a reduction in tumor necrosis factor induction or inhibition of phospholipase A2 in addition to its antifungal activity. 25 refs., 2 figs.},
doi = {10.1016/0360-3016(94)90566-5},
url = {https://www.osti.gov/biblio/86487}, journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 4,
volume = 29,
place = {United States},
year = {Fri Jul 01 00:00:00 EDT 1994},
month = {Fri Jul 01 00:00:00 EDT 1994}
}