Maczynski Marcin, Artym Jolanta, Kocieba Maja, Sockacka-Cwikla Aleksandra, Drozd-Szczygiel Ewa, Ryng Stanislaw, Zimecki Michal
Acta Pol Pharm. 2016 Sep;73(5):1201-1211.
The aim of the study was to characterize a series of isoxazole derivatives in several immunological tests in vitro and in vivo, in mouse and human models. The human model included measurement of: viability of peripheral blood mononuclear cells (PBMC), phytohemagglutinin A (PHA)-induced proliferation of PBMC, production of tumor necrosis factor a (TNF a) in whole blood cultures stimulated with lipopolysaccharide (LPS) and growth of SW-948 and L1210 tumor cell lines. Experiments in mice encompassed the following tests: secondary, humoral immune response splenocytes to sheep erythrocytes (SRBC) in vitiv, delayed type hypersensitivity (DTH) to ovalbumin (OVA) and carrageenan-induced foot edema. All compounds were non-toxic against PMBC and displayed differential, dose-dependent suppressive properties in the model of PHA- induced PMBC proliferation. They also exhibited differential, mostly inhibitory effects on TNF a production. The inhibitory actions on growth of tumor cell lines were moderate. M05 (5-amino-3-methyl-N-(4-methyl-benzyl)-4-isoxazolecarboxamide) was most suppressive in the proliferation and TNF a production tests, it was, therefore, selected for in vitro and in vivo studies in the mouse models. The compound inhibited the humoral immune response in vitro, stimulated the inductive phase of DTH in vivo, although it inhibited the eliciting phase of that response. The compound also inhibited the carrageenan skin reaction. M05 combines strong anti-proliferative and anti-inflammatory activities, it is therefore attractive for further studies in more advanced animal models as a potential therapeutic.
本研究的目的是在小鼠和人类模型中，通过一系列体外和体内免疫学试验对一系列异恶唑衍生物进行特性描述。人类模型包括测量：外周血单核细胞（PBMC）的活力、植物血凝素A（PHA）诱导的PBMC增殖、脂多糖（LPS）刺激的全血培养物中肿瘤坏死因子α（TNFα）的产生以及SW - 948和L1210肿瘤细胞系的生长。小鼠实验包括以下试验：对绵羊红细胞（SRBC）的二次体液免疫反应脾细胞体外实验、对卵清蛋白（OVA）的迟发型超敏反应（DTH）以及角叉菜胶诱导的足肿胀。所有化合物对PMBC均无毒，并在PHA诱导的PMBC增殖模型中表现出不同的、剂量依赖性的抑制特性。它们还对TNFα的产生表现出不同的、大多为抑制性的作用。对肿瘤细胞系生长的抑制作用中等。M05（5 - 氨基 - 3 - 甲基 - N - （4 - 甲基 - 苄基） - 4 - 异恶唑甲酰胺）在增殖和TNFα产生试验中抑制作用最强，因此被选用于小鼠模型的体外和体内研究。该化合物在体外抑制体液免疫反应，在体内刺激DTH的诱导期，尽管它抑制该反应的激发期。该化合物还抑制角叉菜胶皮肤反应。M05兼具强大的抗增殖和抗炎活性，因此作为一种潜在的治疗药物，在更高级的动物模型中进行进一步研究具有吸引力。
