Corral L G, Muller G W, Moreira A L, Chen Y, Wu M, Stirling D, Kaplan G
Celgene Corporation, Warren, New Jersey, USA.
Mol Med. 1996 Jul;2(4):506-15.
Tumor necrosis factor alpha (TNF alpha) is thought to mediate both protective and detrimental manifestations of the inflammatory response. Recently, thalidomide (alpha-N-phthalimidoglutarimide) was shown to partially inhibit monocyte TNF alpha production (by 50-70%) both in vivo and in vitro. More efficient inhibition of TNF alpha may, however, be necessary to rescue the host from more acute and extensive toxicities of TNF alpha-mediated inflammation.
Three structural analogues of thalidomide were selected for study based on increased activity against TNF alpha production. The parent drug and the analogs were tested in vitro in human peripheral blood mononuclear cell cultures for their effects on lipopolysaccharide (LPS) induced cytokine protein and mRNA production using ELISAs and Northern blot hybridization. The in vitro effects of the drugs were then confirmed in vivo in a mouse model of LPS induced lethality.
The new compounds (two esters and one amide) showed increased inhibition of TNF alpha production by LPS-stimulated human monocytes, relative to the parent drug thalidomide. The analogs and the parent drug enhanced the production of interleukin 10 (IL-10), but had little effect on IL-6 and IL-1 beta protein and mRNA production. When tested in vivo, the amide analog protected 80% of LPS-treated mice against death from endotoxin induced shock.
Analogs of thalidomide designed to better inhibit TNF alpha production in vitro have correspondingly greater efficacy in vivo. These finding may have therapeutic implication for the treatment of human diseases characterized by acute and extensive TNF alpha production such as tuberculous meningitis or toxic shock.
肿瘤坏死因子α（TNFα）被认为可介导炎症反应的保护性和有害性表现。最近，沙利度胺（α-N-邻苯二甲酰亚胺基戊二酸）已显示在体内和体外均可部分抑制单核细胞TNFα的产生（抑制率为50%-70%）。然而，可能需要更有效地抑制TNFα，才能使宿主从TNFα介导的炎症更急性和广泛的毒性中获救。
基于对TNFα产生的活性增强，选择了三种沙利度胺的结构类似物进行研究。使用酶联免疫吸附测定法（ELISAs）和Northern印迹杂交，在人外周血单核细胞培养物中对母体药物及其类似物进行体外测试，以研究它们对脂多糖（LPS）诱导的细胞因子蛋白和mRNA产生的影响。然后在LPS诱导致死性的小鼠模型中对药物的体外作用进行体内验证。
相对于母体药物沙利度胺，新化合物（两种酯和一种酰胺）对LPS刺激的人单核细胞产生TNFα的抑制作用增强。这些类似物和母体药物增强了白细胞介素10（IL-10）的产生，但对IL-6和IL-1β蛋白及mRNA的产生影响很小。在体内进行测试时，酰胺类似物可保护80%接受LPS治疗的小鼠免于死于内毒素诱导的休克。
设计用于在体外更好地抑制TNFα产生的沙利度胺类似物在体内具有相应更高的疗效。这些发现可能对治疗以急性和大量产生TNFα为特征的人类疾病（如结核性脑膜炎或中毒性休克）具有治疗意义。
