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 »
- Authors:
-
- 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}
}