Nojima S, Kobuchi H, Saibara T, Yasuda T, Utsumi K
Department of Cell Chemistry, Okayama University Medical School, Japan.
Physiol Chem Phys Med NMR. 1995;27(2):77-89.
It is now generally accepted that human tumor necrosis factor-alpha (hTNF-alpha) affects not only tumor cells but also normal cells, providing critical tissue damage. hTNF-alpha also enhanced the response of polymorphonuclear neutrophils (PMN) by its priming action and resulted in the increased generation of active oxygen which in turn may be responsible for the tissue injury. Seeking a conventional drug to attenuate the cytolytic activity of tumor necrosis factor (TNF-alpha) and thereby prevent excessive tissue injury, we focused on the cytolytic action of hTNF-alpha against L929 cells, which are sensitive to TNF-alpha, and found that flecainide acetate [N-(2-piperidylmethyl) 1,5-bis-(2,2,2-trifluoroethoxy) benzamide acetate] inhibited specifically the cytolytic action of hTNF-alpha against L929 cells. Flecainide acetate also specifically inhibited the priming action of hTNF-alpha which enhance the formylmethionyl-leucyl-phenylalanine (FMLP)-induced receptor-mediated superoxide (O.2-) generation of human peripheral polymorphonuclear neutrophils (hPMN). The ID50 values for hTNF-alpha induced cytotoxicity in L929 cells and hTNF-alpha primed FMLP-induced O.2- generation of hPMN were 30 and 50-60 microM, respectively. However, the drug does not inhibit the FMLP- or phorbol myristate acetate (PMA)-induced O.2- generation of nonprimed hPMN and has a weak cytotoxic effect on L929 cells. From these results, it is concluded that flecainide acetate suppressed specifically the action of hTNF-alpha.
现在人们普遍认为，人类肿瘤坏死因子-α（hTNF-α）不仅影响肿瘤细胞，还影响正常细胞，会造成严重的组织损伤。hTNF-α还通过其启动作用增强了多形核中性粒细胞（PMN）的反应，并导致活性氧生成增加，这反过来可能是组织损伤的原因。为了寻找一种传统药物来减弱肿瘤坏死因子（TNF-α）的细胞溶解活性，从而防止过度的组织损伤，我们重点研究了hTNF-α对L929细胞（对TNF-α敏感）的细胞溶解作用，发现醋酸氟卡尼[N-(2-哌啶基甲基)1,5-双-(2,2,2-三氟乙氧基)苯甲酰胺醋酸盐]能特异性抑制hTNF-α对L929细胞的细胞溶解作用。醋酸氟卡尼还能特异性抑制hTNF-α的启动作用，该启动作用可增强甲酰甲硫氨酰-亮氨酰-苯丙氨酸（FMLP）诱导的人外周多形核中性粒细胞（hPMN）受体介导的超氧化物（O₂⁻）生成。hTNF-α诱导L929细胞产生细胞毒性以及hTNF-α启动FMLP诱导hPMN产生O₂⁻的半数抑制浓度（ID50）值分别为30和50 - 60微摩尔。然而，该药物并不抑制FMLP或佛波酯（PMA）诱导的未启动hPMN产生O₂⁻，并且对L929细胞具有较弱的细胞毒性作用。从这些结果可以得出结论，醋酸氟卡尼能特异性抑制hTNF-α的作用。
