Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA.
Cancer Chemother Pharmacol. 2010 Oct;66(5):869-80. doi: 10.1007/s00280-009-1232-1. Epub 2010 Jan 23.
This study was designed to test the ability of the Bcl-2 family inhibitor ABT-263 to potentiate commonly used chemotherapeutic agents and regimens in hematologic tumor models.
Models of B-cell lymphoma and multiple myeloma were tested in vitro and in vivo with ABT-263 in combination with standard chemotherapeutic regimens, including VAP, CHOP and R-CHOP, as well as single cytotoxic agents including etoposide, rituximab, bortezomib and cyclophosphamide. Alterations in Bcl-2 family member expression patterns were analyzed to define mechanisms of potentiation.
ABT-263 was additive with etoposide, vincristine and VAP in vitro in the diffuse large B-cell lymphoma line (DLBCL) DoHH-2, while rituximab potentiated its activity in SuDHL-4. Bortezomib strongly synergized with ABT-263 in the mantle cell lymphoma line Granta 519. Treatment of DoHH-2 with etoposide was associated with an increase in Puma expression, while bortezomib upregulated Noxa expression in Granta 519. Combination of ABT-263 with cytotoxic agents demonstrated superior tumor growth inhibition and delay in multiple models versus cytotoxic therapy alone, along with significant improvements in tumor response rates.
Inhibition of the Bcl-2 family of proteins by ABT-263 enhances the cytotoxicity of multiple chemotherapeutics in hematologic tumors and represents a promising addition to the therapeutic arsenal for treatment of these diseases.
本研究旨在测试 Bcl-2 家族抑制剂 ABT-263 增强血液肿瘤模型中常用化疗药物和方案的能力。
在体外和体内使用 ABT-263 联合标准化疗方案（包括 VAP、CHOP 和 R-CHOP）以及单药细胞毒药物（包括依托泊苷、利妥昔单抗、硼替佐米和环磷酰胺）对 B 细胞淋巴瘤和多发性骨髓瘤模型进行测试。分析 Bcl-2 家族成员表达模式的改变，以确定增强作用的机制。
ABT-263 与依托泊苷、长春新碱和 VAP 在弥漫性大 B 细胞淋巴瘤系（DLBCL）DoHH-2 中具有体外相加作用，而利妥昔单抗增强了其在 SuDHL-4 中的活性。硼替佐米与 ABT-263 在套细胞淋巴瘤系 Granta 519 中具有强烈的协同作用。用依托泊苷处理 DoHH-2 会导致 Puma 表达增加，而硼替佐米在 Granta 519 中上调 Noxa 表达。ABT-263 与细胞毒药物的联合治疗在多个模型中与单独细胞毒治疗相比，表现出优越的肿瘤生长抑制和延迟作用，并且肿瘤反应率显著提高。
ABT-263 抑制 Bcl-2 家族蛋白增强了血液肿瘤中多种化疗药物的细胞毒性，代表了治疗这些疾病的治疗武器库中的一种有前途的补充。
