Free Radical and Radiation Biology Program, Department of Radiation Oncology, The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242-1181, USA.
Neoplasia. 2010 Dec;12(12):980-92. doi: 10.1593/neo.101146.
Dexamethasone (Dex) and radiation therapy are established modalities in multiple myeloma. In this study, we propose a novel combination of Dex plus radiation that shows superior clonogenic cell killing and apoptosis of myeloma cells and selectively eliminates myeloma cells when cocultured with bone marrow stromal cells (BMSCs). Dex was found to inhibit the release of interleukin-6 from irradiated BMSCs, which is an established myeloma cell proproliferative cytokine. In 5TGM1 model, the combination of Dex with skeletal targeted radiotherapy (153-Sm-EDTMP) prolonged median survival time and inhibited radiation-induced myelosuppression. A two-cycle treatment of Dex plus 153-Sm-EDTMP was well tolerated and further improved median survival time. Mechanistically, Dex increased superoxide and hydrogen peroxide production and augmented radiation-induced oxidative stress and cell death of myeloma cells. In contrast, Dex inhibited radiation-induced increase in pro-oxidant levels and enhanced the clonogenic survival in normal hematopoietic stem and progenitor cells. Treatment with either N-acetylcysteine or the combination of polyethylene glycol (PEG)-conjugated copper, zinc-superoxide dismutase, and PEG-catalase significantly protected myeloma cells from Dex-induced clonogenic death. Overall, these results demonstrate that Dex in combination with radiotherapy enhances the killing of myeloma cells while protecting normal bone marrow hematopoiesis through a mechanism that involves selective increases in oxidative stress.
地塞米松（Dex）和放射疗法是多发性骨髓瘤的既定治疗方式。在这项研究中，我们提出了一种新的 Dex 联合放射疗法，该疗法显示出对骨髓瘤细胞集落形成细胞杀伤和凋亡的优越性，并且在与骨髓基质细胞（BMSCs）共培养时可选择性地消除骨髓瘤细胞。发现 Dex 可抑制辐照 BMSCs 释放白细胞介素-6，后者是一种已确立的骨髓瘤细胞促增殖细胞因子。在 5TGM1 模型中，Dex 与骨骼靶向放射疗法（153-Sm-EDTMP）联合使用可延长中位生存时间并抑制放射诱导的骨髓抑制。两周期的 Dex 加 153-Sm-EDTMP 治疗耐受性良好，并进一步延长了中位生存时间。从机制上讲，Dex 增加了超氧化物和过氧化氢的产生，并增强了放射诱导的骨髓瘤细胞氧化应激和细胞死亡。相比之下，Dex 抑制了放射诱导的促氧化剂水平增加，并增强了正常造血干细胞和祖细胞的集落形成存活能力。用 N-乙酰半胱氨酸或聚乙二醇（PEG）缀合的铜、锌超氧化物歧化酶和 PEG 过氧化氢酶的组合治疗可显著保护骨髓瘤细胞免受 Dex 诱导的集落形成死亡。总的来说，这些结果表明，Dex 联合放射疗法通过涉及选择性增加氧化应激的机制增强了骨髓瘤细胞的杀伤作用，同时保护了正常骨髓造血。
