Selection of Novel Analogs of Thalidomide with Enhanced Tumor Necrosis Factor α Inhibitory Activity
Selection of Novel Analogs of Thalidomide with Enhanced Tumor Necrosis Factor α Inhibitory Activity
复制标题
具有增强肿瘤坏死因子α抑制活性的沙利度胺新型类似物的选择
作者：
L. Corral;G. Muller;A. Moreira;Yuxi Chen;Mingdan Wu;D. Stirling;G. Kaplan
肿瘤坏死因子α(肿瘤坏死因子α)被认为在炎症反应中既有保护性的也有破坏性的表现。最近，沙利度胺(α-n-邻苯二甲酰亚胺-戊二酰亚胺)在体内和体外都能部分抑制单核细胞肿瘤坏死因子α的产生(50-70%)。然而，更有效地抑制肿瘤坏死因子α可能是拯救宿主免受肿瘤坏死因子α介导的炎症的更急性和更广泛的毒性所必需的。材料和方法基于对肿瘤坏死因子α产生的增强的活性，选择了3种沙利度胺的结构类似物进行研究。体外培养人外周血单个核细胞，用ELISAs和Northern印迹杂交检测母药和类似物对内毒素诱导的细胞因子蛋白和信使核糖核酸表达的影响。结果与母药沙利度胺相比，新化合物(两个酯类和一个酰胺类)对内毒素刺激的人单核细胞产生肿瘤坏死因子α的抑制作用增强。类似物和母药均能促进IL-10的产生，但对IL-6和IL-1的β蛋白和基因表达无明显影响。结论反应停类似物在体外能更好地抑制肿瘤坏死因子α的产生，具有较好的体内保护作用。这些发现可能对治疗以急性和广泛产生肿瘤坏死因子α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。
BackgroundTumor necrosis factor α (TNFα) is thought to mediate both protective and detrimental manifestations of the inflammatory response. Recently, thalidomide (α-n–phthalimidoglutarimide) was shown to partially inhibit monocyte TNFα production (by 50–70%) both in vivo and in vitro. More efficient inhibition of TNFα may, however, be necessary to rescue the host from more acute and extensive toxicities of TNFα-mediated inflammation.Materials and MethodsThree structural analogues of thalidomide were selected for study based on increased activity against TNFα 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.ResultsThe new compounds (two esters and one amide) showed increased inhibition of TNFα 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-1β protein and mRNA production. When tested in vivo, the amide analog protected 80% of LPS-treated mice against death from endotoxin induced shock.ConclusionsAnalogs of thalidomide designed to better inhibit TNFα 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 TNFα production such as tuberculous meningitis or toxic shock.
影响因子：
6.4
作者：
SAMPAIO, EP;KAPLAN, G;SARNO, EN
通讯作者：
SARNO, EN
影响因子：
4.4
作者：
C. Tannenbaum;Thomas A. Hamilton
通讯作者：
C. Tannenbaum;Thomas A. Hamilton
内源性 IL-10 可保护小鼠在脓毒性腹膜炎期间免于死亡。
DOI：
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发表时间：
1995
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
vanderPoll,T;Marchant,A;Buurman,WA;Berman,L;Keogh,CV;Lazarus,DD;Nguyen,L;Goldman,M;Moldawer,LL;Lowry,SF
通讯作者：
Lowry,SF