Suitable drug combination with bortezomib for multiple myeloma under stroma-free conditions and in contact with fibronectin or bone marrow stromal cells.
Suitable drug combination with bortezomib for multiple myeloma under stroma-free conditions and in contact with fibronectin or bone marrow stromal cells.
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在无基质条件下并与纤连蛋白或骨髓基质细胞接触的多发性骨髓瘤与硼替佐米的合适药物组合。
DOI：
10.1007/s12185-014-1573-3
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发表时间：
2014
期刊：
影响因子：
2.1
通讯作者：
and Furukawa Y.
中科院分区：
文献类型：
--
作者：
Kikuchi J;Koyama D;Mukai YH;and Furukawa Y.
一些临床试验已经证明硼替佐米与各种抗骨髓瘤药物联合使用的有效性；然而，关于最适合与硼替佐米联合使用的药物，尚无明确的信息。通过等线图分析，我们研究了硼替佐米与四种关键抗骨髓瘤药物（美法兰、环磷酰胺、阿霉素和来那度胺）在不同条件下对三种骨髓瘤细胞系（U266、RPMI8226和KMS-12BM）的联合作用，这些药物代表了硼替佐米与皮质类固醇的主要治疗方案的成分。在所有的培养条件下（液体培养，在纤维连接蛋白包被板上，与骨髓基质细胞共培养），Melphalan与硼替佐米表现出最好的性能，而环磷酰胺与硼替佐米拮抗，尤其是在基质细胞存在的情况下。阿霉素在无基质条件下和与纤维连接蛋白接触时表现出加性作用，但在基质细胞存在时表现出拮抗作用。相比之下，来那度胺与硼替佐米在与基质细胞接触时发挥最有利的作用。与这些结果一致，与其他药物联合硼替佐米相比，美伐兰对caspase-3的激活作用更强。此外，来那度胺与基质细胞接触后，硼替佐米诱导的CHOP上调很容易增强。本研究结果可能为骨髓瘤患者选择硼替佐米为基础的治疗方案提供基础信息。
Several clinical trials have demonstrated the effectiveness of bortezomib in combination with various anti-myeloma agents; however, no definitive information is available regarding drugs best suited for use in combination with bortezomib. Using isobologram analysis, we investigated the combined effects of bortezomib with four key anti-myeloma drugs (melphalan, cyclophosphamide, doxorubicin and lenalidomide), which represent components of major bortezomib-based regimens with corticosteroids, in three myeloma cell lines (U266, RPMI8226 and KMS-12BM) under various conditions. Melphalan showed the best performance with bortezomib under all culture conditions tested (liquid culture, on fibronectin-coated plates, and co-culture with bone marrow stromal cells), whereas cyclophosphamide was antagonistic with bortezomib especially in the presence of stromal cells. Doxorubicin showed additive effects under stroma-free conditions and in contact with fibronectin, but was rather antagonistic in the presence of stromal cells. In contrast, lenalidomide exerted the most favorable effect with bortezomib in contact with stromal cells. Consistent with these results, caspase-3 was activated more strongly by melphalan than by other agents in combination with bortezomib. Moreover, bortezomib-induced up-regulation of CHOP was readily enhanced by lenalidomide in contact with stromal cells. The present findings may provide fundamental information for the selection of bortezomib-based regimens for myeloma patients.