Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity
Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity
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DOI：
10.1038/sj.leu.2403205
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发表时间：
2004-02-01
期刊：
影响因子：
11.4
通讯作者：
Falkenburg, JHF
中科院分区：
文献类型：
--
作者：
Jedema, I;Barge, RMY;Falkenburg, JHF
Gemtuzumab Ozogamicin （GO/Mylotarg(R)）的多中心II期试验显示，复发性急性髓系白血病患者的总有效率为30%，该试验由CD33抗体与细胞毒性药物calicheamicin连接组成。然而，未观察到白血病细胞CD33表达与氧化石墨烯治疗反应之间的明显相关性。我们分析了氧化石墨烯诱导细胞死亡的CD33特异性以及氧化石墨烯对CD33阴性恶性肿瘤的影响。我们证明由临床相关的氧化石墨烯浓度诱导的裂解部分是CD33介导的，而非CD33介导的氧化石墨烯的有效摄取可以通过内吞作用发生。与这些结果一致，我们在NOD/SCID小鼠模型中体外和体内观察到氧化石墨烯介导的人cd33阴性急性淋巴细胞白血病细胞死亡。最后，对氧化石墨烯诱导的细胞死亡的敏感性至少部分取决于白血病细胞的激活状态，处于细胞周期激活阶段的细胞在CD33特异性氧化石墨烯内化、CD33分子的重新表达以及通过内吞作用非CD33介导的氧化石墨烯摄取方面都是最有效的。总之，这些数据为氧化石墨烯在cd33阳性和cd33阴性具有内吞能力的恶性肿瘤中的疗效提供了机制见解，并为使用氧化石墨烯治疗具有内吞能力的恶性肿瘤提供了理论依据。
Multicenter phase II trials with Gemtuzumab Ozogamicin (GO/Mylotarg(R)), consisting of a CD33 antibody linked to the cytotoxic drug calicheamicin, have shown a 30% overall response rate in relapsed acute myeloid leukemia patients. However, no clear correlation was observed between CD33 expression on leukemic blasts and response to GO therapy. We analyzed the CD33 specificity of GO-induced cell death and the effect of GO on CD33-negative malignancies. We demonstrate that lysis induced by clinically relevant GO concentrations is partially CD33 mediated, and that efficient non-CD33-mediated GO uptake can occur via endocytosis. In agreement with these results, we observed GO-mediated death of human CD33-negative acute lymphoblastic leukemia cells both in vitro and in vivo in an NOD/SCID mouse model. Finally, sensitivity to GO-induced cell death was at least partially determined by the activation status of leukemic cells, with cells in activated phases of the cell cycle being most effective in both CD33-specific GO internalization, renewed expression of CD33 molecules, and non-CD33-mediated GO uptake via endocytosis. In conclusion, these data provide mechanistic insight into the efficacy of GO in CD33-positive as well as in CD33-negative malignancies with endocytic capacity, and provide a rationale for the use of GO in the treatment of malignancies with endocytic capacity.