Enhancing immunotoxin cell-killing activity via combination therapy with ABT-737.
Enhancing immunotoxin cell-killing activity via combination therapy with ABT-737.
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DOI：
10.3109/10428194.2011.569961
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发表时间：
2011-06
影响因子：
2.6
通讯作者：
Pastan I
中科院分区：
文献类型：
--
作者：
Fitzgerald DJ;Moskatel E;Ben-Josef G;Traini R;Tendler T;Sharma A;Antignani A;Mussai F;Wayne A;Kreitman RJ;Pastan I
免疫毒素是一种抗体-毒素融合蛋白，用于杀死癌细胞，在其表面显示特定的靶抗原。值得注意的是，针对毛细胞白血病的CD22免疫毒素在大约60%的I/II期试验患者中产生了完全缓解。由于尚不清楚的原因，40%的患者反应较差。此外，其他cd22阳性恶性肿瘤患者尚未实现完全缓解。在试图了解对免疫毒素治疗的“耐药性”时，提出了许多具有挑战性的问题。这些问题包括剂量不足、产生中和性抗免疫毒素抗体、难以接近恶性细胞以及对毒素杀伤的抵抗。在设计免疫毒素时，我们采用截断的假单胞菌外毒素，它能酶灭蛋白质合成并在敏感细胞中产生细胞死亡。为了开始解决毒素抗性，我们已经探索了与bh3模拟物ABT-737的联合治疗。我们的研究结果表明，免疫毒素- abt组合通常比单独使用任何一种化合物表现出更大的杀伤活性，并且在某些情况下克服了耐药性。高水平的促生存Bcl-2蛋白的表达可能有助于毒素抗性。
Immunotoxins are antibody–toxin fusion proteins directed to kill cancer cells displaying specific target antigens on their surface. Remarkably, immunotoxins directed to CD22 on hairy cell leukemia have produced complete remissions in approximately 60% of patients enrolled in phase I/II trials. For reasons that are not yet clear, 40% of patients responded less well. In addition, patients with other CD22-positive malignancies have not yet achieved complete remissions. In trying to understand ‘resistance’ to immunotoxin therapy, a number of challenging issues have been raised. These include insufficient dosing, the production of neutralizing anti-immunotoxin antibodies, poor access to malignant cells, and resistance to toxin killing. In designing immunotoxins, we employ truncated Pseudomonas exotoxin, which enzymatically inactivates protein synthesis and produces cell death in sensitive cells. To begin to address toxin resistance we have explored combination therapy with the BH3-only mimetic, ABT-737. Our results indicate that immunotoxin–ABT combinations often exhibit greater killing activity than either compound alone and in some instances overcome resistance. Expression of high levels of prosurvival Bcl-2 proteins may contribute to toxin resistance.
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DOI：
10.1073/pnas.0708101104
发表时间：
2007-10-23
影响因子：
11.1
作者：
Zhang, Yujian;Xiang, Laiman;Pastan, Ira
通讯作者：
Pastan, Ira
影响因子：
5.3
作者：
Du, Xing;Youle, Richard J.;Pastan, Ira
通讯作者：
Pastan, Ira
DOI：
10.1073/pnas.0804851105
发表时间：
2008-08-12
影响因子：
11.1
作者：
Onda, Masanori;Beers, Richard;Pastan, Ira
通讯作者：
Pastan, Ira
影响因子：
5.7
作者：
Traini R;Ben-Josef G;Pastrana DV;Moskatel E;Sharma AK;Antignani A;Fitzgerald DJ
通讯作者：
Fitzgerald DJ
影响因子：
6.4
作者：
Andersson, Y;Juell, S;Fodstad, O
通讯作者：
Fodstad, O