The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction
The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction
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DOI：
10.1182/blood.v99.3.1038
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发表时间：
2002-02-01
期刊：
影响因子：
20.3
通讯作者：
Reed, JC
中科院分区：
文献类型：
--
作者：
Byrd, JC;Kitada, S;Reed, JC
利妥昔单抗是一种针对CD20的嵌合单抗，对非霍奇金淋巴瘤(NHL)和慢性淋巴细胞白血病(CLL)有显著的治疗活性。对于这种治疗性抗体，人们提出了多种不同于细胞毒化疗的肿瘤细胞毒性途径，包括抗体依赖的细胞毒性和补体介导的细胞溶解。这份报告描述了部分接受利妥昔单抗治疗的慢性淋巴细胞白血病患者在输注利妥昔单抗后立即体内激活了白血病细胞中caspase-9、caspase-3和聚(ADP-核糖)聚合酶(PARP)的裂解。这表明，在利妥昔单抗治疗后，通过类似于氟达拉滨和其他化疗药物的途径进行的细胞凋亡复杂地参与了肿瘤细胞的血液清除，体内有caspase-3激活和PARP裂解的患者在治疗后的白血病细胞计数明显低于那些没有激活caspase的患者。抗凋亡蛋白XIAP和Mcl-1的显著下调也被注意到，这可能在一定程度上解释了利妥昔单抗在体内如何使CLL细胞对化疗的细胞毒效应敏感。这些发现表明，基于抗体的体内治疗对CLL患者的疗效部分依赖于诱导细胞凋亡，并为研究肿瘤细胞的抗体耐药机制提供了另一个重点领域。(C)2002年，由美国血液病学会公布。
Rituximab is a chimeric monoclonal antibody directed at CD20 with significant activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). A variety of pathways of tumor cytotoxicity different from cytotoxic chemotherapy have been proposed for this therapeutic antibody including antibody-dependent cellular cytotoxicity and complement-mediated cell lysis. This report describes that a proportion of patients with CLL receiving rituximab treatment have in vivo activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP) cleavage in blood leukemia cells immediately following infusion of rituximab. This suggests that apoptosis using a pathway similar to fludarabine and other chemotherapeutic agents is intricately involved in the blood elimination of tumor cells after rituximab treatment, Patients having caspase-3 activation and PARP cleavage in vivo had a significantly lower blood leukemia cell count after treatment as compared to those without caspase activation. Significant down-modulation of the antiapoptotic proteins XIAP and Mcl-1 was also noted, possibly explaining in part how rituximab sensitizes CLL cells to the cytotoxic effect of chemotherapy in vivo. These findings suggest that the therapeutic benefit of antibody-based therapy in vivo for patients with CLL depends in part on induction of apoptosis and provides another area of focus for studying mechanisms of antibody-resistance in neoplastic cells. (C) 2002 by The American Society of Hematology.