Basic and clinical research on Tumor Necrosis Factor (TNF)

探讨了肿瘤坏死因子的细胞毒作用机制。肿瘤坏死因子敏感细胞株和肿瘤坏死因子耐药细胞株均不能从培养上清液中吸附肿瘤坏死因子活性。对肿瘤坏死因子敏感细胞的酶消化不能降低肿瘤坏死因子的细胞毒活性。肿瘤坏死因子诱导肿瘤细胞内源性溶酶体活性增强。加入肿瘤坏死因子后，易感肿瘤细胞在一段时间后呼吸减少，随后呼吸再次增加。超氧化物歧化酶、叠氮化钠和氟化钠可显著增加肿瘤坏死因子的细胞毒作用。肿瘤坏死因子可增加靶肿瘤细胞中氧自由基的产生。这些结果表明髓过氧化物酶系统和糖酵解，即线粒体功能和能量代谢的重要性。在体外获得细胞毒性的肿瘤坏死因子浓度是体内坏死性反应的血液浓度的10~100倍。这种差异的原因之一被认为是肿瘤坏死因子引起了涉及内皮细胞的变化。在组织病理学上，肿瘤坏死的机制可能是由于血液循环障碍而导致的出血性脑梗塞，并伴有微血管损伤，表现为肿瘤组织血管内充血和多发纤维蛋白血栓。除肿瘤组织外，其他脏器均未见病理改变。然而，肿瘤坏死因子会导致肉芽组织的坏死。在体外实验中，肿瘤坏死因子对血管内皮细胞有明显的生理影响，如形态改变、生长抑制或细胞毒作用。

The mechanism of cytotoxic action and necrotizing action of TNF was examined. TNF activity could not be adsorbed by both TNF sensitive cell lines and TNF resistant cell lines from supernatant of the culture medium. Enzyme digestion of TNF sensitive cells failed to decrease the cytotoxic activity of TNF. TNF induced enhancement of the endogenous lysosome activity of tumor cells. Following addition of TNF, susceptible tumor cells revealed a decreased respiration after a certain period, and the respiration subsequently increased again. Superoxidase dismutase, sodium azide and sodium fluoride markedly increased the cytotoxicity of TNF. TNF increased the generation of <O(_2^-)> and other oxygen radicals in target tumor cells. These results suggest the importance of the myeloperoxidase system and glycolysis, that is, mitochondrial function and energy metabolism. The concentration of TNF acquiring in vitro cytotoxicity was 10 to 100 times higher than that reached in the blood for the in vivo necrotizing reaction. One of the reasons for this discrepancy is considered to be that TNF gives rise to changes involving endothelial cells. Histopathologically, the mechanism of tumor necrosis induced by TNF administration may be a hemorrhagic infarct due to circulatory disturbance associated with a microvascular injury manifested by hyperemia and multiple fibrin thrombi in vascular channels of tumor tissue. There were no pathologic changes in organs other than tumor tissue. However, TNF causes necrosis of granulation tissues. In vitro experiment, TNF exerts distinct physiological influences, such as morphological alteration, growth inhibition or cytotoxicity on the vascular endothelial cells.