Blockade of bulky lymphoma-associated CD55 expression by RNA interference overcomes resistance to complement-dependent cytotoxicity with rituximab
Blockade of bulky lymphoma-associated CD55 expression by RNA interference overcomes resistance to complement-dependent cytotoxicity with rituximab
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DOI：
10.1111/j.1349-7006.2006.00139.x
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发表时间：
2006-01-01
期刊：
影响因子：
5.7
通讯作者：
Hatake, K
中科院分区：
文献类型：
--
作者：
Terui, Y;Sakurai, T;Hatake, K
最近，抗-CD 20（利妥昔单抗）和抗-Her 2/neu（曲妥珠单抗）抗体已被开发并分别应用于恶性淋巴瘤和乳腺癌的治疗。然而，巨块型淋巴瘤是已知的是耐利妥昔单抗治疗，这需要克服。收集30例非霍奇金淋巴瘤患者的新鲜淋巴瘤细胞，用流式细胞术检测CD 20和CD 55的表达，并进行补体依赖性细胞毒性（CDC）试验。使用临床样本，利妥昔单抗以肿瘤大小依赖的方式降低CDC敏感性（r =-0.895，P < 0.0001），但不以CD 20依赖的方式降低CDC敏感性（r =-0.076，P = 0.6807）。一种补体抑制蛋白CD 55，导致了大体积淋巴瘤对利妥昔单抗CDC的耐药性。利妥昔单抗对CDC敏感性的降低在统计学上依赖于CD 55表达（r =-0.927，P < 0.0001），并且使用临床样本，肿瘤大小与CD 55表达之间的关系显示出显著的正相关（r = 0.921，P < 0.0001）。为了通过在巨大淋巴瘤块中高表达CD 55来克服对利妥昔单抗的抗性，从对应于CD 55 cDNA的核酸1-380的DNA序列设计小干扰RNA（siRNA）。这种siRNA的引入降低了乳腺癌细胞系SK-BR 3和复发性淋巴瘤患者的CD 20阳性细胞中的CD 55表达;对CDC的抗性也被抑制。这一观察结果为我们提供了一种新的策略，以抑制单克隆抗体治疗的大规模疾病相关的耐药性。
Recently, anti-CD20 (rituximab) and anti-Her2/neu (trastuzumab) antibodies have been developed and applied to the treatment of malignant lymphoma and breast cancer, respectively. However, bulky lymphoma is known to be resistant to rituximab therapy, and this needs to be overcome. Fresh lymphoma cells were collected from 30 patients with non-Hodgkin's lymphoma, the expression of CD20 and CD55 was examined by flow cytometry, and complement-dependent cytotoxicity (CDC) assays were carried out. Susceptibility to CDC with rituximab was decreased in a tumor size-dependent manner (r = -0.895, P < 0.0001), but not in a CD20-dependent manner (r = -0.076, P = 0.6807) using clinical samples. One complement-inhibitory protein, CD55, contributed to bulky lymphoma-related resistance to CDC with rituximab. A decrease in susceptibility to CDC with rituximab was statistically dependent on CD55 expression (r = -0.927, P < 0.0001) and the relationship between tumor size and CD55 expression showed a significant positive correlation (r = 0.921, P < 0.0001) using clinical samples. To overcome the resistance to rituximab by high expression of CD55 in bulky lymphoma masses, small interfering RNA (siRNA) was designed from the DNA sequence corresponding to nucleic acids 1-380 of the CD55 cDNA. Introduction of this siRNA decreased CD55 expression in the breast cancer cell line SK-BR3 and in CD20-positive cells of patients with recurrent lymphoma; resistance to CDC was also inhibited. This observation gives us a novel strategy to suppress bulky disease-related resistance to monoclonal antibody treatment.