Tumor necrosis factor as a pharmacological target.
Tumor necrosis factor as a pharmacological target.
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DOI：
10.1385/mb:31:3:239
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发表时间：
2005-11
影响因子：
2.6
通讯作者：
Cerami A
中科院分区：
文献类型：
--
作者：
Ghezzi P;Cerami A
肿瘤坏死因子（tumor necrosis factor， TNF）顾名思义，1985年克隆出来的肿瘤坏死因子（tumor necrosis factor， TNF）最初被描述为一种来源于巨噬细胞的内源性介质，在体外可诱导实体肿瘤出血性坏死并杀死部分肿瘤细胞系。不幸的是，由于其毒性，其作为抗癌药物的前景受到了影响，这一点在肿瘤坏死因子的第一次临床试验中很快就清楚了。几乎在同一时间，肿瘤坏死因子作为抗癌药物被开发出来，很明显，肿瘤坏死因子与一种与败血症相关的恶病质介质是相同的，这种介质被称为恶病质。该研究发现TNF实际上是脓毒症的主要致死介质，并发表了大量文章表明TNF抑制细菌内毒素的毒性作用，这种毒性作用现在被描述为全身性炎症反应。尽管到目前为止，抗TNF在败血症中的临床试验尚未成功，但毫无疑问，由于临床环境的复杂性，这些研究最终导致了TNF作为关键炎症介质的鉴定，以及抗TNF分子（可溶性受体和抗体）的开发，用于治疗包括类风湿关节炎和克罗恩病在内的重要疾病。另一方面，TNF及其相关分子诱导细胞死亡的机制已被深入研究，这些知识可能在未来为提高TNF在癌症中的治疗指标提供手段。
As indicated by its name, tumor necrosis factor (TNF), cloned in 1985, was originally described as a macrophage-derived endogenous mediator that can induce hemorrhagic necrosis of solid tumors and kill some tumor cell lines in vitro. Unfortunately, its promising use as an anticancer agent was biased by its toxicity, which was clear soon from the first clinical trials with TNF in cancer. Almost at the same time TNF was being developed as an anticancer drug, it became clear that TNF was identical to a mediator responsible for cachexia associated with sepsis, which was termed cachectin. This research led to the finding that TNF is, in fact, the main lethal mediator of sepsis and to the publication of a huge number of articles showing that TNF inhibits the toxic effects of bacterial endotoxins, which are now described as systemic inflammatory response. Although the clinical trials with anti-TNF in sepsis have not been successful thus far, undoubtedly as a result of the complexity of this clinical setting, these studies ultimately led to the identification of TNF as a key inflammatory mediator and to the development of anti-TNF molecules (soluble receptors and antibodies) for important diseases including rheumatoid arthritis and Crohn’s disease. On the other side, the mechanisms by which TNF and related molecules induce cell death have been studied in depth, and their knowledge might, in the future, suggest means of improve the therapeutic index of TNF in cancer.