Pro-apoptotic therapy with the oligonucleotide Genasenseâ„¢ (oblimersen sodium) targeting Bcl-2 protein expression enhances the biological anti-tumour activity of rituximab
Pro-apoptotic therapy with the oligonucleotide Genasenseâ„¢ (oblimersen sodium) targeting Bcl-2 protein expression enhances the biological anti-tumour activity of rituximab
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DOI：
10.1111/j.1365-2141.2004.05239.x
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发表时间：
2004-12-01
影响因子：
6.5
通讯作者：
Czuczman, MS
中科院分区：
文献类型：
--
作者：
Ramanarayanan, J;Hernandez-Ilizaliturri, FJ;Czuczman, MS
非霍奇金淋巴瘤 (NHL) 患者的治疗已出现新策略。反义寡核苷酸（ASO）和单克隆抗体（mAb）疗法虽然被证明是安全有效的，但尚未证明作为单一药物使用时具有疗效。我们在积极的临床前模型中测试了针对 Bcl-2 (G3139) 的创新组合策略，涉及各种 mAb 和 ASO。与对照组相比，G3139在最佳转染条件下使淋巴瘤细胞增殖率降低60-75%。此外，在 Bcl-2 蛋白下调后，用 Genasense 处理的 Raji (25%) 和 DHL-4 细胞 (30%) 出现细胞凋亡。与单独利妥昔单抗治疗的对照相比，G3139 对 Bcl-2 的下调与更高程度的利妥昔单抗相关、补体介导的细胞毒性和抗体依赖性细胞毒性相关。对严重联合免疫缺陷 (SCID) 小鼠的体内研究清楚地证明了 G3139 和利妥昔单抗之间的协同活性。在每次利妥昔单抗剂量之前用 G3139 连续两天治疗患有淋巴瘤的 SCID 小鼠，与单独使用药物或对照治疗相比，可实现更好的疾病控制和生存。我们的研究结果表明，G3139 下调 Bcl-2，然后给予利妥昔单抗是一种有效的抗肿瘤策略，与改善患有淋巴瘤的 SCID 小鼠的生存率相关。
New strategies have evolved in the treatment of patients with non-Hodgkin's lymphoma (NHL). Anti-sense oligonucleotides (ASO) and monoclonal antibody (mAb) therapy, though proven to be safe and effective, have not demonstrated to be curative when used as single agents. We tested an innovative combination strategy involving various mAbs and ASO against Bcl-2 (G3139) in aggressive preclinical models. G3139, under optimal transfection conditions, decreased the proliferation rate of lymphoma cells by 60-75% when compared with controls. In addition, apoptosis was demonstrated in Raji (25%) and DHL-4 cells (30%) treated with Genasense following downregulation of Bcl-2 protein. Downregulation of Bcl-2 by G3139 was associated with a higher degree of rituximab-associated, complement-mediated cytotoxicity and antibody dependent cellular cytotoxicity when compared with rituximab alone-treated controls. In vivo studies in severe combined immunodeficiency (SCID) mice clearly demonstrated synergistic activity between G3139 and rituximab. Treatment of lymphoma-bearing SCID mice with G3139 for two consecutive days prior to each rituximab dose resulted in better disease control and survival than treatment with either agent alone or controls. Our findings suggest that Bcl-2 downregulation by G3139, followed by the administration of rituximab is an efficient anti-tumour strategy associated with improved survival in lymphoma-bearing SCID mice.