Preliminary in vivo evaluation of the protein transduction domain-modified ATTEMPTS approach in enhancing asparaginase therapy
Preliminary in vivo evaluation of the protein transduction domain-modified ATTEMPTS approach in enhancing asparaginase therapy
复制标题
DOI：
10.1002/jbm.a.32204
复制
发表时间：
2009-10-01
影响因子：
4.9
通讯作者：
Yang, Victor C.
中科院分区：
文献类型：
--
作者：
Li, Yong Tao;Kwon, Young Min;Yang, Victor C.
天冬酰胺酶（ASNase）是一种酶药物，目前批准用于诱导缓解急性淋巴细胞白血病（ALL）患者的治疗。ASNase的细胞毒性作用源自其消耗天冬酰胺的能力，天冬酰胺是某些类型的白血病细胞蛋白质合成和存活所需的必需氨基酸。尽管其在ALL患者中提高疾病缓解率和延长完全缓解持续时间方面的功效，但是ASNase疗法仍然被许多严重的毒性作用所混淆，特别是对与高蛋白质产生相关的器官（例如，肝脏、胰腺），这是由于天冬酰胺的系统性消耗。本文提供的是我们先前建立的ATTEMPTS蛋白递送系统的修改版本，其具有允许肿瘤特异性细胞内递送ASNase的潜力，从而允许显著降低ASNase诱导的全身毒性。在之前的论文中，我们已经证明了这种肝素/鱼精蛋白调节的TAT介导的系统在将ASNase直接递送到ASNase敏感的小鼠淋巴瘤细胞中的体外可行性。在这篇文章中，我们进一步验证了该系统在动物体内的适用性窝藏ASNase封装的L5178 Y淋巴瘤细胞。初步结果显示，接种含有TAT-ASNase的L5178 Y细胞的动物表现出比那些携带L5178 Y细胞但没有包裹ASNase的动物延长的存活率接近13%。此外，TAT-ASNase处理的小鼠还显示出比对照组显著改善的血液学和肝脏组织学状态。这些发现为使用改良的ATTEMPTS递送系统实现增强的ASNase治疗带来了希望。(C)2008 Wiley Periodicals，Inc. J Biomed Mater Res 91A：209-220，2009
Asparaginase (ASNase) is an enzyme drug presently approved for the induction of remission in the treatment of patients with acute lymphoblastic leukemia (ALL). The cytotoxic effect of ASNase is derived from its ability to deplete asparagine, an essential amino acid required by certain types of leukemia cells for protein synthesis and survival. Despite its efficacy in enhancing disease remission rate and prolonging complete remission duration in ALL patients, ASNase therapy is nevertheless confounded by a number of serious toxic effects, particularly to organs associated with high protein production (e.g., liver, pancreas), due to the systemic depletion of asparagine. Presented herein is a modified version of our previously established ATTEMPTS protein delivery system that carries the potential to permit a tumor specific, intracellular delivery of ASNase, thereby allowing for a significant reduction of ASNase-induced systemic toxicity. In a previous paper, we already demonstrated the in vitro feasibility of this heparin/protamine-regulated, TAT-mediated system in delivering ASNase directly into ASNase-sensitive murine lymphoma cells. In this article, we further validated the in vivo applicability of this system in animals harboring ASNase-encapsulated L5178Y lymphoma cells. Preliminary results showed that animals inoculated with L5178Y cells containing TAT-ASNase exhibited an extended survival rate of similar to 13% over those harboring L5178Y cells without the encapsulation of ASNase. Furthermore, the TAT-ASNase-treated mice also displayed a significantly improved hematological and liver histological status than the control groups. These findings bring promise to the use of the modified ATTEMPTS delivery system in achieving enhanced ASNase therapy. (C) 2008 Wiley Periodicals, Inc. J Biomed Mater Res 91A: 209-220, 2009