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Genetically Modified DR5-Specific TRAIL Variant DR5-B Revealed Dual Antitumor and Protumoral Effect in Colon Cancer Xenografts and an Improved Pharmacokinetic Profile.
Translational Oncology ( IF 4.5 ) Pub Date : 2020-03-27 , DOI: 10.1016/j.tranon.2020.100762
Anne V Yagolovich 1 , Artem A Artykov 1 , Tatiana A Karmakova 2 , Maria S Vorontsova 2 , Andrey A Pankratov 2 , Alexander A Andreev-Andrievsky 3 , Dmitry A Dolgikh 1 , Mikhail P Kirpichnikov 1 , Marine E Gasparian 4
Affiliation  

Despite the weak clinical efficacy of TRAIL death receptor agonists, a search is under way for new agents that more efficiently activate apoptotic signaling. We previously created a TRAIL DR5-selective variant DR5-B without affinity for the DR4, DcR1, DcR2, and OPG receptors and increased proapoptotic activity in tumor cells. Here we showed that DR5-B significantly inhibited tumor growth in HCT116 and Caco-2 but not in HT-29 xenografts. The antitumor activity of DR5-B was 2.5 times higher in HCT116 xenografts compared to TRAIL. DR5-B at a dose of 2 or 10 mg/kg/d for 10 days inhibited tumor growth in HCT116 xenografts by 26% or 50% respectively, and increased animal survival. Unexpectedly, DR5-B at a higher dose (25 mg/kg/d) inhibited tumor growth only during the first 8 days of drug exposure, while at the end of the monitoring, no effect or even slight stimulation of tumor growth was observed. The pharmacokinetic parameters of DR5-B were comparable to those of TRAIL, except that the half-life was 3.5 times higher. Thus, enhancing TRAIL selectivity to DR5 may increase both antitumor and proliferative activities depending on the concentration and administration regimens.



中文翻译:

转基因的DR5特异的TRAIL变体DR5-B在结肠癌异种移植中显示出双重抗肿瘤和促癌作用,并改善了药代动力学。

尽管TRAIL死亡受体激动剂的临床疗效较弱,但仍在寻找能更有效地激活凋亡信号的新药物。我们先前创建了对DR4,DcR1,DcR2和OPG受体没有亲和力的TRAIL DR5-选择性变体DR5-B,并增加了肿瘤细胞的促凋亡活性。在这里,我们显示DR5-B显着抑制HCT116和Caco-2中的肿瘤生长,但不抑制HT-29异种移植物中的肿瘤生长。与TRAIL相比,HCT116异种移植物中DR5-B的抗肿瘤活性高2.5倍。DR5-B的剂量为2或10 mg / kg / d,持续10天,分别抑制HCT116异种移植物中的肿瘤生长26%或50%,并提高了动物存活率。出乎意料的是,较高剂量(25 mg / kg / d)的DR5-B仅在药物暴露的前8天抑制肿瘤生长,而在监测结束时,没有观察到影响或什至轻微刺激肿瘤生长。DR5-B的药代动力学参数与TRAIL相当,除了半衰期高3.5倍。因此,取决于浓度和给药方案,增强对DR5的TRAIL选择性可以增加抗肿瘤和增殖活性。

更新日期:2020-03-27
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