Effective treatment of a murine model of adult T-cell leukemia using depsipeptide and its combination with unmodified daclizumab directed toward CD25
Effective treatment of a murine model of adult T-cell leukemia using depsipeptide and its combination with unmodified daclizumab directed toward CD25
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DOI：
10.1182/blood-2008-04-149658
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发表时间：
2009-02-05
期刊：
影响因子：
20.3
通讯作者：
Waldmann, Thomas A.
中科院分区：
文献类型：
--
作者：
Chen, Jing;Zhang, Meili;Waldmann, Thomas A.
成人 T 细胞白血病 (ATL) 是由人类 T 细胞嗜淋巴细胞病毒 I (HTLV-1) 引起的，是一种表达 CD4、CD25 的白血病和淋巴瘤细胞的侵袭性恶性肿瘤。 ATL 尚无公认的治疗方法。 Depsipeptide 是一种组蛋白脱乙酰酶抑制剂，已在白血病和淋巴瘤中显示出主要的抗肿瘤作用。在这项研究中，我们在人类 ATL 小鼠模型中研究了单独使用缩酚肽以及与达克珠单抗（人源化抗 Tac）联合使用的治疗效果。 Met-1 ATL模型是通过将离体白血病细胞腹腔注射到非肥胖糖尿病/严重联合免疫缺陷小鼠中建立的。通过可溶性 IL-2R-α (sIL-2R-α) 和可溶性 β(2)-微球蛋白 (β(2)mu) 血清水平监测，无论是缩酚肽，每隔一天给予 0.5 mg/kg，持续 2 周，还是达克珠单抗，每周 100 μg，持续 4 周，均抑制肿瘤生长，并延长了患有白血病的小鼠的生存期（P < .001）。 .001) 与对照组相比。与单独使用缩肽或达克珠单抗组相比，缩肽与达克珠单抗的组合增强了抗肿瘤作用，如 sIL-2R-α 和 β(2)mu 水平以及白血病小鼠的存活率所示 (P < .001)。缩酚肽与达克珠单抗联合显着提高了治疗效果，支持了该联合治疗 ATL 的临床试验。 （血。2009；113：1287-1293）
Adult T-cell leukemia (ATL) is caused by human T-cell lymphotropic virus I (HTLV-1) and is an aggressive malignancy of CD4, CD25-expressing leukemia, and lymphoma cells. There is no accepted curative therapy for ATL. Depsipeptide, a histone deacetylase inhibitor, has demonstrated major antitumor effects in leukemias and lymphomas. In this study, we investigated the therapeutic efficacy of depsipeptide alone and in combination with daclizumab (humanized anti-Tac) in a murine model of human ATL. The Met-1 ATL model was established by intraperitoneal injection of ex vivo leukemic cells into nonobese diabetic/severe combined immunodeficiency mice. Either depsipeptide, given at 0.5 mg/kg every other day for 2 weeks, or daclizumab, given at 100 mu g weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of soluble IL-2R-alpha (sIL-2R-alpha) and soluble beta(2)-microglobulin (beta(2)mu) (P < .001), and prolonged survival of the leukemia-bearing mice (P < .001) compared with the control group. Combination of depsipeptide with daclizumab enhanced the antitumor effect, as shown by both sIL-2R-alpha and beta(2)mu levels and survival of the leukemia-bearing mice, compared with those in the depsipeptide or daclizumab alone groups (P < .001). The significantly improved therapeutic efficacy by combining depsipeptide with daclizumab supports a clinical trial of this combination in the treatment of ATL. (Blood. 2009; 113: 1287-1293)