摘要

BACKGROUND: Rituximab is used in the treatment of CD20+ B cell lymphomas and other B cell lymphoproliferative disorders. Its clinical efficacy might be further improved by combinations with other drugs such as statins that inhibit cholesterol synthesis and show promising antilymphoma effects. The objective of this study was to evaluate the influence of statins on rituximab-induced killing of B cell lymphomas. METHODS AND FINDINGS: Complement-dependent cytotoxicity (CDC) was assessed by MTT and Alamar blue assays as well as trypan blue staining, and antibody-dependent cellular cytotoxicity (ADCC) was assessed by a 51Cr release assay. Statins were found to significantly decrease rituximab-mediated CDC and ADCC of B cell lymphoma cells. Incubation of B cell lymphoma cells with statins decreased CD20 immunostaining in flow cytometry studies but did not affect total cellular levels of CD20 as measured with RT-PCR and Western blotting. Similar effects are exerted by other cholesterol-depleting agents (methyl-beta-cyclodextrin and berberine), but not filipin III, indicating that the presence of plasma membrane cholesterol and not lipid rafts is required for rituximab-mediated CDC. Immunofluorescence microscopy using double staining with monoclonal antibodies (mAbs) directed against a conformational epitope and a linear cytoplasmic epitope revealed that CD20 is present in the plasma membrane in comparable amounts in control and statin-treated cells. Atomic force microscopy and limited proteolysis indicated that statins, through cholesterol depletion, induce conformational changes in CD20 that result in impaired binding of anti-CD20 mAb. An in vivo reduction of cholesterol induced by short-term treatment of five patients with hypercholesterolemia with atorvastatin resulted in reduced anti-CD20 binding to freshly isolated B cells. CONCLUSIONS: Statins were shown to interfere with both detection of CD20 and antilymphoma activity of rituximab. These studies have significant clinical implications, as impaired binding of mAbs to conformational epitopes of CD20 elicited by statins could delay diagnosis, postpone effective treatment, or impair anti-lymphoma activity of rituximab.

译文

背景: 利妥昔单抗用于治疗 CD20 b细胞淋巴瘤和其他 b细胞淋巴增生性疾病。它的临床疗效可以通过与其他药物如他汀类药物的联合进一步提高,这些药物抑制胆固醇合成并显示出有希望的抗淋巴瘤作用。本研究的目的是评估他汀类药物对利妥昔单抗诱导的 b细胞淋巴瘤杀伤的影响。方法和结果: 通过 MTT 和 Alamar blue 试验以及台盼蓝染色和抗体依赖性细胞毒性 (ADCC) 评估补体依赖性细胞毒性 (CDC) 通过 51Cr 释放试验进行评估。发现他汀类药物可显著降低利妥昔单抗介导的 b细胞淋巴瘤细胞的 CDC 和 ADCC。用他汀类药物孵育 b细胞淋巴瘤细胞减少了流式细胞术研究中的 CD20 免疫染色,但不影响用 RT-PCR 和蛋白质印迹法测量的 CD20 的总细胞水平。其他胆固醇消耗剂 (甲基-β-环糊精和黄连素) 也发挥了类似的作用,但菲利平 III, 表明利妥昔单抗介导的 CDC 需要质膜胆固醇而不是脂筏的存在。使用单克隆抗体 (mAbs) 双重染色的免疫荧光显微镜检查针对构象表位和线性细胞质表位,显示 CD20 在对照和他汀类药物处理的细胞中以相当数量存在于质膜中。原子力显微镜和有限的蛋白水解表明,他汀类药物通过胆固醇消耗,诱导 CD20 的构象变化,导致 anti-CD20 单克隆抗体的结合受损。通过对 5 名患有高胆固醇血症的患者进行短期治疗而诱导的体内胆固醇降低导致 anti-CD20 与新分离的 b细胞的结合减少。结论: 他汀类药物显示干扰 CD20 的检测和利妥昔单抗的抗淋巴瘤活性。这些研究具有重要的临床意义,因为单克隆抗体与他汀类药物诱导的 CD20 构象表位的结合受损可能会延迟诊断、推迟有效治疗或损害利妥昔单抗的抗淋巴瘤活性。

rituximab

肿瘤 免疫治疗 药物
概述  :  

利妥昔单抗是1997年在美国上市的一种癌症治疗药物,是罗氏公司的又一个抗癌靶向药物,其商品名为美罗华。利妥昔单抗主要用于治疗复发或耐药性中央型淋巴瘤(国际工作分类B、C和D亚型的B细胞非霍奇金淋巴瘤)的治疗。CD20阳性弥漫大B细胞性非霍奇金淋巴瘤(DLBCL)应与标准CHOP化疗(环磷酰胺、阿霉素、长春新碱、强的松)8个周期联合治疗,同时目前已获批作为晚期结肠癌的一线用药。该药为淡黄色澄明液体,无异物,絮状物及沉淀,给药方式为静脉注射。作用机制利妥昔单抗是一种嵌合鼠/人的单克隆抗体,该抗体

rituximab

释    义   利妥昔单抗;利妥昔单克隆抗体

例    句   This is the first study demonstrating a clear benefit of rituximab maintenance following a rituximab-containing induction regimen.  这是首个显示出在进行了包含美罗华的诱导疗法之后采用美罗华维持疗法有明显益处的试验。

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