THE TOXIC EFFECTS OF TUMOR-NECROSIS-FACTOR INVIVO AND THEIR PREVENTION BY CYCLOOXYGENASE INHIBITORS
THE TOXIC EFFECTS OF TUMOR-NECROSIS-FACTOR INVIVO AND THEIR PREVENTION BY CYCLOOXYGENASE INHIBITORS
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DOI：
10.1073/pnas.84.12.4273
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发表时间：
1987-06-01
影响因子：
11.1
通讯作者：
GOLDBERG, AL
中科院分区：
文献类型：
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作者：
KETTELHUT, IC;FIERS, W;GOLDBERG, AL
肿瘤坏死因子（Tumor necrosis factor， TNF）是巨噬细胞的产物，作为抗癌药物正在积极研究中。然而，这种药物可能毒性很大，并与内毒素休克的发病机制有关。经静脉注射人重组TNF (4 .mu。G / G)，生长中的大鼠表现出不同寻常的生理反应，并在2-4小时内全部死亡。在1小时内，TNF使其急剧下降2.5度。C)体温升高，血浆前列腺素E2水平大幅升高。最初血糖升高，但2小时后出现严重低血糖。使用tnf治疗的动物还出现腹泻、紫绀和严重的代谢性酸中毒。在TNF治疗前单次注射环氧合酶抑制剂吲哚美辛或布洛芬完全阻止了快速死亡，最终死亡率降低了70%。这些药物阻断前列腺素E2的产生，防止体温过低、血糖变化、酸中毒和其他症状。由于内毒素注射后也有类似的生理变化报道，我们的数据支持TNF的产生是脓毒性休克发生的关键因素。这些发现还表明，前列腺素或血栓素的产生增加在内源性休克中是重要的，并认为环加氧酶抑制剂应在其治疗中有用。在体外实验中，吲哚美辛不能阻断TNF对几种转化细胞系（HeLa、Me 180或L929）的细胞毒性作用。因此，TNF与环加氧酶抑制剂的联合使用可能允许对癌症患者更安全地给予高剂量的这种多肽。
Tumor necrosis factor (TNF) is a macrophage product under active study as an anticancer drug. However, this agent can be very toxic and has been implicated in the pathogenesis of endotoxic shock. After intravenous injection of human recombinant TNF (4 .mu.g/g), growing rats showed an unusual constellation of physiological responses, and all died with in 2-4 hr. In 1 hr, TNF caused a sharp fall (2.5.degree. C) in body temperature and a large increase in plasma prostaglandin E2 levels. Blood glucose initially increased, but then a profound hypoglycemia developed by 2 hr. The TNF-treated animals also showed diarrhea, cyanosis, and a severe metabolic acidosis. A single injection of the cyclooxygenase inhibitors indomethacin or ibuprofen before the TNF treatment completely prevented the rapid killing and reduced eventually lethality by 70%. These agents blocked prostaglandin E2 production and prevented the hypothermia, changes in blood glucose, acidosis, and other symptoms. Since similar physiological changes have been reported after endotoxin injection, our data support the suggestion that TNF production is a critical factor in the development of septic shock. These findings also indicate that increased production of prostaglandins or thromboxanes is important in endotoxic shock and argue that cyclooxygenase inhibitors should be useful in its therapy. Indomethacin did not block the cytotoxic effects of TNF in vitro on several transformed cell lines (HeLa, Me 180, or L929). Therefore, combined use of TNF with a cyclooxygenase inhibitor may allow safer administration of high doses of this polypeptide to cancer patients.