Apoptotic-regulatory and complement-protecting protein expression in chronic lymphocytic leukemia: Relationship to in vivo rituximab resistance
Apoptotic-regulatory and complement-protecting protein expression in chronic lymphocytic leukemia: Relationship to in vivo rituximab resistance
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DOI：
10.1200/jco.2003.06.012
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发表时间：
2003-04-15
影响因子：
45.3
通讯作者：
Byrd, JC
中科院分区：
文献类型：
--
作者：
Bannerji, R;Kitada, S;Byrd, JC
目的：利妥昔单抗在慢性淋巴细胞白血病（CLL）患者中具有临床活性，并且有多种可能的作用机制，包括细胞凋亡、补体依赖的细胞溶解（CDC）以及抗体依赖的细胞毒性（ADCC）。在此我们研究在CLL患者中促进对细胞凋亡和CDC产生抗性的治疗前生物学特征，并将其与基于利妥昔单抗治疗的临床结果相关联。
患者与方法：对21例参与一项前瞻性单药利妥昔单抗试验的CLL患者的治疗前样本进行检测，以确定细胞凋亡和CDC调节蛋白的定量表达，并将这些蛋白的表达水平与临床结果相关联。
结果：在可获取样本的21例患者中，10例获得部分缓解，11例对利妥昔单抗治疗无反应。Bcl - 2、Mcl - 1、XIAP的平均治疗前表达以及Bcl - 2/Bax的比值在无反应患者中较高，但与有反应的患者相比无统计学差异。相反，治疗前Mcl - 1/Bax比值在无反应患者中显著升高（0.82 ± 0.28比0.39 ± 0.29，P < 0.016）。尽管CD55和CD59的治疗前表达与对利妥昔单抗治疗的反应无关，但在治疗结束时未从血液中清除的CLL细胞中观察到的CD59水平显著高于基线水平（P = 0.02）。
结论：这些数据表明Mcl - 1/Bax比值的基线表达，而非CD55和CD59，可预测CLL患者对利妥昔单抗治疗的临床反应。进一步研究CLL中细胞凋亡受阻作为对利妥昔单抗产生抗性的潜在机制似乎是有必要的。（C）2003年美国临床肿瘤学会
Purpose: Rituximab has clinical activity in patients with chronic lymphocytic leukemia (CLL) and has a variety of proposed mechanisms, including apoptosis, complement-dependent cell lysis (CDC), and antibody-dependent cellular cytotoxicity (ADCC). Here we examine pretreatment biologic features that promote resistance to apoptosis and CDC in CLL patients and correlate it with clinical outcome to rituximab-based therapy.Patients and Methods: Pretreatment samples from 21 CLL patients treated on a prospective, single-agent rituximab trial were examined for quantitative expression of apoptotic and CDC regulatory proteins, and the level of expression of these proteins was correlated with clinical outcome.Results: Of the 21 patents for whom samples were available, 10 attained a partial response and 11 failed to respond to rituximab therapy. The mean pretreatment expression of Bcl-2, Mcl-1, XIAP, and the ratio of Bcl-2/Bax were higher but not statistically increased in nonresponding patients versus those responding to treatment. In contrast, the pretreatment Mcl-1/Bax ratio was significantly elevated (0.82 +/- 0.28 v 0.39 +/- 0.29, P < .016) in nonresponding patients compared with patients responding to rituximab therapy. Although pretreatment expression of CD55 and CD59 was not associated with response to rituximab therapy, significantly higher levels of CD59 were observed in the CLL cells that were not cleared from the blood at completion of therapy than the level observed at baseline levels (P = .02).Conclusion: These data indicate that baseline expression of the Mcl-1/Bax ratio, but not CD55 and CD59, predict for clinical response to rituximab therapy in CLL patients. Further study of disrupted apoptosis in CLL as a potential mechanism of resistance to rituximab appears warranted. (C) 2003 by American Society of Clinical Oncology.