蛋白酶体抑制剂:小说类的有力和有效的抗肿瘤药物。

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亚当斯J, Palombella VJ, Sausville EA,约翰逊J, Destree,拉撒路DD,马斯河J,棱角CS,普拉卡什年代,艾略特PJ

蛋白酶体抑制剂:小说类的有力和有效的抗肿瘤药物。

癌症研究》1999年6月1日,59(11):2615 - 22所示。

PubMed ID

10363983 (在PubMed

]

文摘

ubiquitin-proteasome通路中起关键作用的调节降解的蛋白质参与细胞周期控制和肿瘤的生长。就是说,这种蛋白质的降解应该对肿瘤的生长产生深远的影响,以引起细胞凋亡。为了验证这个假设,我们开发了一系列新颖的蛋白酶体抑制剂,以ps - 341,我们在这里描述。由美国国家癌症研究所体外屏幕,ps - 341有大量针对范围广泛的人类肿瘤细胞细胞毒性,包括前列腺癌细胞系。曲泽前列腺细胞系,因此,选择进一步检查ps - 341的抗肿瘤活性。体外、ps - 341抒发蛋白酶体抑制,从而增加细胞内特定蛋白的水平,包括细胞周期蛋白依赖性激酶抑制剂,p21。此外,接触此类细胞的ps - 341使他们积累G2-M阶段的细胞周期,随后进行细胞凋亡,表明核凝结和聚(ADP-ribose)聚合酶乳沟。后每周静脉输液治疗的ps - 341小鼠轴承曲泽肿瘤,明显降低肿瘤负荷(60%)是观察到体内。ps - 341直接注射到肿瘤还导致大幅下降(70%)与40%的药物治疗小鼠肿瘤体积没有检测到肿瘤的研究。ps - 341的研究还表明,静脉输液管理导致快速和广泛分布的ps - 341,最高水平确定在肝脏和胃肠道和皮肤和肌肉的最低水平。 Modest levels were found in the prostate, whereas there was no apparent penetration of the central nervous system. An assay to follow the biological activity of the PS-341 was established and used to determine temporal drug activity as well as its ability to penetrate tissues. As such, PS-341 was shown to penetrate PC-3 tumors and inhibit intracellular proteasome activity 1.0 h after i.v. dosing. These data illustrate that PS-341 not only reaches its biological target but has a direct effect on its biochemical target, the proteasome. Importantly, the data show that inhibition of this target site by PS-341 results in reduced tumor growth in murine tumor models. Together, the results highlight that the proteasome is a novel biochemical target and that inhibitors such as PS-341 represent a unique class of antitumor agents. PS-341 is currently under clinical evaluation for advanced cancers.

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药物

Bortezomib