Experimental study enhancing the chemosensitivity of multiple myeloma to melphalan by using a tissue-specific APE 1-silencing RNA expression vector
Experimental study enhancing the chemosensitivity of multiple myeloma to melphalan by using a tissue-specific APE 1-silencing RNA expression vector
复制标题
利用组织特异性APE 1沉默RNA表达载体增强多发性骨髓瘤对马法兰化疗敏感性的实验研究
DOI：
10.3816/clm.2007.n.006
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发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Wang, Dong
中科院分区：
文献类型：
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作者：
Yang, Zhen-Zhou;Chen, Xing-Hua;Wang, Dong
目的：多发性骨髓瘤（multiple myeloma， MM）由于对化疗药物产生耐药性，至今仍是一种不治之症。作为克服多发性骨髓瘤肿瘤细胞耐药性和/或使肿瘤细胞对目前使用的化疗药物敏感的一种手段，我们研究了人无尿嘧啶/无嘧啶内切酶1 （APE1）在多发性骨髓瘤患者耐药性和预后中的作用。患者和方法：通过使用32例多发性骨髓瘤患者和10名正常志愿者的骨髓标本分析多发性骨髓瘤细胞。结果：已知临床转归的MM患者骨髓标本中APE1蛋白表达阳性率为65.6%。复发/难治组APE1 2级以上表达阳性率明显高于未治疗组。在非癌性疾病患者的骨髓标本中未检测到>2级阳性结果。KM3细胞中APE1蛋白的表达量与美伐兰的剂量和作用时间呈正相关。由于APE1在难愈/复发MM细胞中过表达，我们利用sirna靶向技术降低了KM3细胞中APE1的水平，蛋白水平在24小时内下降到80%-90%，并持续下降72小时。抑制APE1蛋白表达的最佳剂量为3 μ g，抑制时间为2 d。sirna处理的KM3细胞中APE1水平的降低导致细胞对melphalan的敏感性增强。结论：本文的研究结果为治疗复发/难治性MM提供了预后和治疗意义。APE1沉默RNA的结果表明，使用多种分子和方法对APE1进行治疗性调节是可行的。
Purpose: Because of a developing resistance to chemotherapy agents, multiple myeloma (MM) has been an incurable disease until now. As a means to overcome MM tumor cell resistance and/or sensitize tumor cells to chemotherapeutic treatments currently used, we examined the role of human apurinic/apyrimidinic endonuclease 1 (APE1) in resistance and prognosis in patients with MM. Patients and Methods: Multiple myeloma cells were analyzed by using bone marrow specimens from 32 patients with MM and 10 normal volunteers. Results: The positive rate of APE1 protein expression was 65.6% in the bone marrow specimens of patients with MM with known clinical outcome. Positive rate of APE1 expression beyond grade 2 in the relapsed/refractory group was significantly higher than that in the untreated group. No positive results of grade > 2 were detected in bone marrow specimens from patients with noncancerous disease. It was also confirmed that the amount of APE1 protein in KM3 cells was positively correlated with the dose and action time of melphalan. Because APE1 was overexpressed in refractory/relapsed MM cells, siRNA-targeted technology was used to decrease APE1 levels in KM3 cells, with protein levels deceasing to 80%-90% within 24 hours and continuing to decease for 72 hours. The best dose and time of inhibiting expression of APE1 protein were 3 mu g and 2 days long. A decrease in APE1 levels in siRNA-treated KM3 cells led to enhanced cell sensitization to melphalan. Conclusion: The findings herein present prognostic and therapeutic implications for treating relapsed/refractory MM. The APE1-silencing RNA results demonstrate the feasibility of the therapeutic modulation of APE1 using a variety of molecules and approaches.