<br>AS-1411，一种富含鸟苷的寡核苷酸适体，靶向核仁素，可用于治疗癌症，包括急性髓系白血病。,Current opinion in molecular therapeutics

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AS-1411，一种富含鸟苷的寡核苷酸适体，靶向核仁素，可用于治疗癌症，包括急性髓系白血病。
Current opinion in molecular therapeutics Pub Date : 2010-02-01
Fabien Mongelard ₁ , Philippe Bouvet

Affiliation

AS-1411 由 Antisoma plc 开发，是第一个进入 I 期和 II 期临床试验的寡脱氧核苷酸适体，可用于治疗癌症，包括急性髓性白血病 (AML)。作为适体，AS-1411 似乎不参与需要杂交的途径，例如反义效应、siRNA 或三螺旋形成。相反，AS-1411 似乎与核仁素特异性结合，随后内化到肿瘤细胞中。核仁素是一种丰富的蛋白质，其表达与细胞的增殖状态相关：肿瘤和活跃分裂的细胞中核仁素水平较高。由于核仁素的多功能性质，许多次要靶点在 AS-1411 治疗后可能会受到影响。 AS-1411已在微摩尔范围内的浓度下表现出对多种肿瘤细胞系的临床前生长抑制活性，并且在人类来源肿瘤细胞异种移植的小鼠中产生了良好的疗效。在一项针对多部位转移的晚期难治性癌症患者的 I 期临床试验中，AS-1411 是安全的且耐受性良好；此外，两名肾细胞癌患者报告了一名完全缓解和一名持续部分缓解。 AS-1411 与阿糖胞苷联合治疗 AML 患者的 II 期试验表明，该组合优于单独使用阿糖胞苷。因此，AS-1411 似乎是治疗这些病理学癌症的有前途的候选药物。更好地了解该药物的作用机制对于帮助未来的研究至关重要。

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AS-1411, a guanosine-rich oligonucleotide aptamer targeting nucleolin for the potential treatment of cancer, including acute myeloid leukemia.

In development by Antisoma plc, AS-1411 is the first oligodeoxynucleotide aptamer to reach phase I and II clinical trials for the potential treatment of cancers, including acute myelogenous leukemia (AML). As an aptamer, AS-1411 does not appear to engage in hybridization-requiring pathways such as antisense effect, siRNA or triple helix formation. Instead, AS-1411 appears to bind to nucleolin specifically, and is subsequently internalized into the tumor cell. Nucleolin is an abundant protein, with expression that is correlated with the proliferative status of the cell: nucleolin levels are higher in tumors and actively dividing cells. Because of the multifunctional nature of nucleolin, it is probable that many secondary targets are affected following treatment with AS-1411. AS-1411 has demonstrated preclinical growth inhibition activity against a wide variety of tumor cell lines at concentrations in the micromolar range, and resulted in good efficacy in mice xenografted with tumor cells of human origin. In a phase I clinical trial in patients with advanced, refractory cancers with metastases at multiple sites, AS-1411 was safe and well tolerated; in addition, one complete response and one ongoing partial response were reported in two patients with renal cell carcinoma. A phase II trial of AS-1411 in combination with cytarabine in patients with AML demonstrated the combination to be superior to cytarabine alone. Thus, AS-1411 appears to be a promising candidate for cancer treatment in these pathologies. A greater understanding of the mechanism of action of this agent is essential to aid in future research.

更新日期：2019-11-01

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