Tipifarnib and bortezomib are synergistic and overcome cell adhesion-mediated drug resistance in multiple myeloma and acute myeloid leukemia
Tipifarnib and bortezomib are synergistic and overcome cell adhesion-mediated drug resistance in multiple myeloma and acute myeloid leukemia
复制标题
DOI：
10.1158/1078-0432.ccr-05-1792
复制
发表时间：
2006-01-15
影响因子：
11.5
通讯作者：
Beaupre, DM
中科院分区：
文献类型：
--
作者：
Yanamandra, N;Colaco, NM;Beaupre, DM
在多发性骨髓瘤和急性髓细胞白血病（AML）的临床前模型中已经确定，骨髓微环境提供了对化疗和死亡受体介导的细胞凋亡的保护。这种形式的耐药性，称为从头耐药性，发生独立于长期暴露于癌症相关治疗，并可能促进多药耐药性的发展。因此，鉴定可以克服环境介导的抗性的化合物或药物组合是主要的兴趣。在这项研究中，我们研究了tipifarnib（Zarnestra，以前的R115777）与硼替佐米（Velcade，以前的PS-341）组合在多发性骨髓瘤和AML微环境模型中的活性。该组合被证明在悬浮培养中处理的多发性骨髓瘤和AML细胞系中具有协同作用。即使在对替吡法尼相对耐药的肿瘤细胞中，也保持了组合活性。当多发性骨髓瘤和AML细胞粘附于纤连蛋白时，替吡法尼和硼替佐米也有效，这提供了该组合克服细胞粘附介导的耐药性（CAM-DR）的证据。重要的是，激活内质网应激反应增强，并与凋亡和逆转CAM-DR。多发性骨髓瘤和AML细胞与骨髓基质细胞共培养也保持敏感，虽然基质粘附的肿瘤细胞部分保护（相对于细胞悬浮液或纤连蛋白粘附）。使用transwell装置对该组合进行评价，结果显示基质细胞产生保护性可溶性因子。正在进行调查，以确定所涉及的细胞因子和/或生长因子。总之，我们的研究为在多发性骨髓瘤和AML患者中测试替吡法尼和硼替佐米组合的试验提供了临床前原理。
It has been established in preclinical models of multiple myeloma and acute myeloid leukemia (AML) that the bone marrow microenvironment provides protection from chemotherapy- and death receptor-mediated apoptosis. This form of resistance, termed de novo drug resistance, occurs independent of chronic exposure to cancer-related therapies and likely promotes the development of multidrug resistance. Consequently, it is of major interest to identify compounds or drug combinations that can overcome environment-mediated resistance. In this study, we investigated the activity of tipifarnib (Zarnestra, formerly R115777) combined with bortezomib (Velcade, formerly PS-341) in microenvironment models of multiple myeloma and AML. The combination proved to be synergistic in multiple myeloma and AML cell lines treated in suspension culture. Even in tumor cells relatively resistant to tipifarnib, combined activity was maintained. Tipifarnib and bortezomib were also effective when multiple myeloma and AML cells were adhered to fibronectin, providing evidence that the combination overcomes cell adhesion-mediated drug resistance (CAM-DR). Of importance, activation of the endoplasmic reticulum stress response was enhanced and correlated with apoptosis and reversal of CAM-DR. Multiple myeloma and AML cells cocultured with bone marrow stromal cells also remained sensitive, although stromal-adhered tumor cells were partially protected (relative to cells in suspension or fibronectin adhered). Evaluation of the combination using a transwell apparatus revealed that stromal cells produce a protective soluble factor. Investigations are under way to identify the cytokines and/or growth factors involved. In summary, our study provides the preclinical rationale for trials testing the tipifarnib and bortezomib combination in patients with multiple myeloma and AML.