Pralatrexate Is Synergistic with the Proteasome Inhibitor Bortezomib in In vitro and In vivo Models of T-Cell Lymphoid Malignancies
Pralatrexate Is Synergistic with the Proteasome Inhibitor Bortezomib in In vitro and In vivo Models of T-Cell Lymphoid Malignancies
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DOI：
10.1158/1078-0432.ccr-10-0671
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发表时间：
2010-07-15
影响因子：
11.5
通讯作者：
O'Connor, Owen A.
中科院分区：
文献类型：
--
作者：
Marchi, Enrica;Paoluzzi, Luca;O'Connor, Owen A.
目的：普拉曲沙（10-炔丙基-10-去氮杂氨基蝶呤）是一种抗叶酸剂，由于对还原型叶酸载体（RFC-1）和叶酸-聚谷氨酰合酶的亲和力更高，因此具有改善的细胞摄取和保留。根据PROPEL数据，普拉曲沙是第一个批准用于复发性和难治性外周T细胞淋巴瘤患者的药物。硼替佐米是一种蛋白酶体抑制剂，在T细胞淋巴瘤患者中显示出一定的活性。实验设计：细胞毒性试验，包括协同作用的数学分析、流式细胞术、免疫印迹和异种移植严重联合免疫缺陷-米色小鼠模型，用于探索普拉曲沙单独和与硼替佐米联合治疗T细胞淋巴恶性肿瘤的体外和体内活性。结果：在体外，普拉曲沙和硼替佐米表现出浓度和时间依赖性细胞毒性对一个广泛的面板的T淋巴瘤细胞系。普拉曲沙与硼替佐米联合使用时，在所有研究的细胞系中均显示出协同作用。当普拉曲沙与硼替佐米联合使用时，在整个小组中也诱导了有效的细胞凋亡和半胱天冬酶激活。对正常外周血单核细胞的细胞毒性研究表明，该组合的毒性并不比单一药物更大。对参与广泛生长和存活途径的蛋白质的Western印迹分析表明，p27、NOXA、HH 3和RFC-1都受到组合的显著调节。在一个严重的联合免疫缺陷-米色小鼠模型转化的皮肤T细胞淋巴瘤，除了普拉曲沙硼替佐米提高疗效相比，无论是药物单独Conclusion：总的来说，这些数据表明，普拉曲沙与硼替佐米组合代表了一种新的和潜在的重要平台，用于治疗T细胞恶性肿瘤。临床癌症研究; 16（14）; 3648-58。(c)2010年AACR。
Purpose: Pralatrexate (10-propargyl-10-deazaaminopterin) is an antifolate with improved cellular uptake and retention due to greater affinity for the reduced folate carrier (RFC-1) and folyl-polyglutamyl synthase. Based on the PROPEL data, pralatrexate was the first drug approved for patients with relapsed and refractory peripheral T-cell lymphoma. Bortezomib is a proteasome inhibitor that has shown some activity in patients with T-cell lymphoma.Experimental Design: Assays for cytotoxicity including mathematical analysis for synergism, flow cytometry, immunoblotting, and a xenograft severe combined immunodeficient-beige mouse model were used to explore the in vitro and in vivo activities of pralatrexate alone and in combination with bortezomib in T-cell lymphoid malignancies.Results: In vitro, pralatrexate and bortezomib exhibited concentration- and time-dependent cytotoxicity against a broad panel of T-lymphoma cell lines. Pralatrexate showed synergism when combined with bortezomib in all cell lines studied. Pralatrexate also induced potent apoptosis and caspase activation when combined with bortezomib across the panel. Cytotoxicity studies on normal peripheral blood mononuclear cells showed that the combination was not more toxic than the single agents. Western blot assays for proteins involved in broad growth and survival pathways showed that p27, NOXA, HH3, and RFC-1 were all significantly modulated by the combination. In a severe combined immunodeficient-beige mouse model of transformed cutaneous T-cell lymphoma, the addition of pralatrexate to bortezomib enhanced efficacy compared with either drug alone.Conclusion: Collectively, these data suggest that pralatrexate in combination with bortezomib represents a novel and potentially important platform for the treatment of T-cell malignancies. Clin Cancer Res; 16(14); 3648-58. (c) 2010 AACR.