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刺激免疫系统对抗癌症

刺激免疫系统对抗癌症

医学 药物 在线翻译
39
2021-03-30 18:14:54

Stimulating the Immune System to Fight Cancer

刺激免疫系统对抗癌症


  Max Planck scientists from Dortmund find immunoregulatory substances with newly developed test system

  来自多特蒙德的Max Planck科学家从新开发的测试系统中找到免疫调节物质

Cancer cells have evolved mechanisms to escape the body's immune defense. Agents that prevent immune escape are attractive targets for the development of new cancer therapies. A group of scientists led by Herbert Waldmann and Slava Ziegler at the Max Planck Institute of Molecular Physiology in Dortmund has now developed a new cell-based test system to identify immunoregulatory modulators. Screening a library of over 150,000 substances revealed several potent substances with unprecedented structure.

癌细胞具有进化的机制来逃避身体的免疫防御。预防免疫逃逸的药剂是有吸引力的新癌症疗法的目标。一群由赫伯特沃尔德曼和斯拉瓦齐格勒领导的科尔克斯普朗克斯·斯普朗特·斯帕克·齐格勒在多特蒙德的Max Planck的分子生理学研究所现已开发出一种新的基于细胞的测试系统,以鉴定免疫调节剂调节剂。筛选超过150,000种物质的文库揭示了几种具有前所未有的结构的有效物质。

用于检测潜在抑制剂的384孔板。.jpg

384-well plate for the detection of potential Inhibitors.

用于检测潜在抑制剂的384孔板。

© MPI of Molecular Physiology

©MPI的分子生理学

Our immune system is very successful when it comes to warding off viruses and bacteria. It also recognizes cancer cells as potential enemies and fights them. However, cancer cells have developed strategies to evade surveillance by the immune system and to prevent immune response.

我们的免疫系统在抵御病毒和细菌方面非常成功。它还将癌细胞视为潜在的敌人并与之对抗。然而,癌细胞已经发展出逃避免疫系统监视和防止免疫反应的策略。

In recent years, fighting cancer with the help of the immune system has entered into clinical practice and gained increasing importance as a therapeutical approach. Current therapies apply so-called immune checkpoint inhibitors. Immune checkpoints are located on the surface of cancer cells and slow down the immune response. Targeting these checkpoints can release this tumour-induced brake. Another strategy developed by cancer cells to escape the immune response is the production of the enzyme indoleamine-2,3-dioxygenase (IDO1), which metabolizes tryptophan into kynurenine and thereby interferes with the immune response in two ways: On the one hand, the depletion of tryptophan negatively impacts the growth of T cells, a central component of the immune response, which seek out and block cancer cells. On the other hand, the produced kynurenin inhibits T cells in the immediate environment of the cancer cells.

近年来,在免疫系统的帮助下,打击癌症已进入临床实践,并获得了对治疗方法的重要性。目前的疗法适用于所谓的免疫检查点抑制剂。免疫检查点位于癌细胞表面上并减慢免疫应答。靶向这些检查点可以释放这种肿瘤诱导的制动器。癌细胞产生的另一种策略以逃避免疫反应是生产酶吲哚氨氨氨氨氨氨酸-2,3-二氧合酶(IDO1),其将色氨酸代谢成犬育植物,从而通过两种方式干扰免疫应答:一方面,色氨酸的耗尽对T细胞的生长产生负面影响,这是一种寻求和阻断癌细胞的免疫应答的中央组分。另一方面,所产生的kynurenin抑制癌细胞的直接环境中的T细胞。

New Inhibitors against IDO1 – The Quest is on

针对IDO1的新抑制剂——探索正在进行中

IDO1 is in the focus of pharmaceutical research because of its cancer-driving effect. However, the search for IDO1 inhibitors has so far been only moderately successful and the first clinically tested IDO1 inhibitor, epacadostat, showed hardly any effect in clinical trials. However, it has not yet been possible to prove whether the inhibitor really blocks IDO1 in the tumour and whether the used dose is sufficient.

由于其癌症驾驶效果,IDO1正处于药物研究的重点。然而,到目前为止,对IDO1抑制剂的搜索仅为中度成功,并且第一个临床测试的IDO1抑制剂EPACADOSTAT在临床试验中表现出几乎没有任何作用。然而,尚不可能证明抑制剂是否真正阻断肿瘤中的IDO1,并且使用过的剂量是否足够。

In drug discovery, experimental test procedures, so-called assays, are employed to search for new disease modulators in large libraries of thousands of compounds. For this purpose, mostly biochemical assays are applied, where a biochemical reaction is impaired if a substance shows an inhibitory effect in the assay. However, this method has certain disadvantages and limitations, as the test takes place in a test tube and not in the natural, cellular environment of the enzyme. For instance, enzymes like IDO1 are less stable and more reactive outside the protective shell of the cell. In addition, cell-free assays cannot detect indirect inhibitors of the enzyme, that for example interfere with its production or with essential co-factors.

在药物发现中,实验试验程序,所谓的分析,用于搜索成千上万化合物的大型文库中的新疾病调制剂。为此目的,施加大多数生物化学测定,如果物质显示测定中的抑制作用,则会损害生化反应。然而,这种方法具有一定的缺点和限制,因为测试在试管中进行,而不是在酶的天然细胞环境中进行。例如,酶像IDO1这样的酶在细胞的保护壳外的稳定性和更具反应性。此外,无细胞的测定不能检测酶的间接抑制剂,例如干扰其生产或具有必要的共同因子。

Novel Cell-Based Assay Discovers IDO1 Inhibitors with Different Mechanisms of Action

新的基于细胞的分析发现IDO1抑制剂具有不同的作用机制

Scientists led by Herbert Waldmann and Slava Ziegler have now developed a cell-based assay for the discovery of new IDO1 inhibitors that overcomes the limitations of cell-free assays. Elisabeth Hennes, PhD student at the Max Planck Institute and first author of the study, employed a sensor that measures the conversion of the IOD1 substrate tryptophan into the metabolic product kynurenine in cell culture and thereby detects IDO1 activity. Based on this test strategy, several highly potent inhibitors with different mechanisms of action were identified from a library of more than 150,000 chemical substances: These include substances that directly switch off IDO1 as well as indirect inhibitors that prevent the production of IDO1 itself or that of its important cofactor heme.

Herbert WaldmannSlava Ziegler领导的科学家现在已经开发了一种基于细胞的测定,用于发现新的IDO1抑制剂,克服了无细胞测定的局限性。 Elisabeth HennesPhd学生在Max Planck Institute和第一个研究的作者中,使用传感器,该传感器测量IOD1谱色氨酸的转化为细胞培养中的代谢产物犬留蛋白,从而检测IDO1活性。基于该试验策略,从150,000个化学物质的文库中鉴定出具有不同作用机制的几种高效抑制剂:这些包括直接关闭IDO1以及间接抑制剂的物质,以防止IDO1本身的产生或其重要的辅影子血红。

"Unfortunately, previous attempts to find a compound that effectively stops the cancer-promoting activity of IDO1 in tumours have met with little success. However, the development of new compounds that can switch off IDO1 via different mechanisms of action could be a promising approach for immunotherapies in the fight against cancer. We hope that our newly developed cell-based assay could contribute to this area of research", says Slava Ziegler.

不幸的是,以前的尝试发现有效地停止肿瘤中IDO1的癌症促进活性的复合物已经满足了一点成功。然而,通过不同的行动机制切断IDO1的新化合物的开发可能是一个有希望的方法争夺癌症的抗击抗击抗击抗争性。我们希望基于细胞的测定可以促进这个研究领域,斯拉瓦齐吉勒说。


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  来源于:mpg


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