Hallahan D E, Virudachalam S, Kufe D W, Weichselbaum R R
Department of Radiation and Cellular Oncology, University of Chicago, IL 60637.
Int J Radiat Oncol Biol Phys. 1994 Jul 1;29(4):777-80. doi: 10.1016/0360-3016(94)90566-5.
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, we 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 cyclooxygenase (indomethacin) 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, bromphenyl bromide, 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. We 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.
先前的研究表明，磷脂酶A2抑制剂可减弱电离辐射诱导的花生四烯酸生成、蛋白激酶C激活，并防止随后肿瘤坏死因子基因的诱导。由于花生四烯酸有助于辐射诱导的肿瘤坏死因子表达，我们分析了改变花生四烯酸代谢的药物对该基因调控的影响。
在照射前1小时，将磷脂酶A2抑制剂奎宁环、溴苯基溴和己酮可可碱，或脂氧合酶抑制剂（酮康唑）或环氧化酶抑制剂（吲哚美辛）添加到细胞培养物中。
每种磷脂酶A2抑制剂（奎宁环、溴苯基溴和己酮可可碱）均减弱了辐射诱导的肿瘤坏死因子基因表达。此外，酮康唑减弱了X射线诱导的肿瘤坏死因子基因表达。相反，吲哚美辛增强了照射后肿瘤坏死因子的表达。
酮康唑减弱辐射诱导的肿瘤坏死因子基因表达这一发现表明，脂氧合酶途径参与肿瘤坏死因子诱导之前的信号转导。照射后吲哚美辛增强肿瘤坏死因子表达表明，环氧化酶产生的前列腺素作为肿瘤坏死因子表达的负调节因子。肿瘤坏死因子诱导的抑制剂可改善放疗的急性和亚急性后遗症。因此，我们提出，酮康唑除了具有抗真菌活性外，还可能通过减少肿瘤坏死因子诱导或抑制磷脂酶A2来减轻急性放射后遗症，如粘膜炎和食管炎。
