Department of Hematology, University Hospital & Cancer Research Center, University of Salamanca P San Vicente, 58-182, 37007 Salamanca, Spain.
Haematologica. 2010 May;95(5):794-803. doi: 10.3324/haematol.2009.015495. Epub 2009 Nov 30.
Combinations of drug treatments based on bortezomib or lenalidomide plus steroids have resulted in very high response rates in multiple myeloma. However, most patients still relapse, indicating the need for novel combination partners to increase duration of response or to treat relapsed disease. We explored the antimyeloma activity of triple combinations of these well-established schemes with panobinostat, a novel deacetylase inhibitor with a multi-targeted profile.
The activity of these combinations was explored in vitro in cell lines by using MTT and annex-in V, ex vivo by flow cytometry, and in vivo using two different murine models of human myeloma: one bearing a subcutaneous plasmacytoma and another with a disseminated myeloma. Moreover, gene expression profiling and immunohistochemical studies were performed.
The addition of panobinostat (LBH589) to dexamethasone and either bortezomib or lenalidomide resulted in clear potentiation in multiple myeloma cell lines, freshly isolated plasma cells, and murine models of multiple myeloma. The quantification of the potency of these combinations by using the Chou-Talalay method showed synergistic combination indices for all of them. This effect derived from the deregulation of a cluster of genes that was completely different from the sum of genes affected by the single agents (895 and 1323 genes exclusively deregulated by panobinostat and dexamethasone plus bortezomib or lenalidomide, respectively). Functional experiments, such as annexin V staining, cell cycle analysis, and immunohistochemical studies also supported this potentiation. Anti-myeloma efficacy was confirmed in an extramedullary plasmacytoma model and a disseminated luciferized model, in which panobinostat also provided a marked benefit in bone disease.
The potent activity, together with the exclusive mechanistic profile, provides the rationale for the clinical evaluation of these drug combinations in multiple myeloma.
硼替佐米或来那度胺联合类固醇的药物治疗组合在多发性骨髓瘤中产生了非常高的缓解率。然而，大多数患者仍会复发，这表明需要新的联合治疗伙伴来延长缓解期或治疗复发疾病。我们研究了这些经过充分验证的方案与新型去乙酰化酶抑制剂帕比司他联合应用的抗骨髓瘤活性，该抑制剂具有多靶向谱。
通过 MTT 和膜联蛋白 V 体外在细胞系中，通过流式细胞术在体外，通过两种不同的人骨髓瘤鼠模型（一种带有皮下浆细胞瘤，另一种带有播散性骨髓瘤）在体内探索这些组合的活性。此外，还进行了基因表达谱分析和免疫组织化学研究。
硼替佐米（LBH589）联合地塞米松和硼替佐米或来那度胺治疗明显增强了多发性骨髓瘤细胞系、新鲜分离的浆细胞和多发性骨髓瘤鼠模型的疗效。通过 Chou-Talalay 方法定量评估这些组合的效力，所有组合的协同组合指数均显示协同作用。这种作用源于一组基因的失调，与单一药物作用所影响的基因（分别由硼替佐米和地塞米松联合硼替佐米或来那度胺单独调节的 895 和 1323 个基因）完全不同。功能实验，如膜联蛋白 V 染色、细胞周期分析和免疫组织化学研究也支持这种增效作用。在髓外浆细胞瘤模型和播散性荧光素化模型中也证实了抗骨髓瘤疗效，其中帕比司他也显著改善了骨病。
这些药物组合的强大活性，加上独特的机制特征，为其在多发性骨髓瘤中的临床评估提供了依据。
