Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Apoptosis. 2011 Jan;16(1):67-74. doi: 10.1007/s10495-010-0545-1.
XIAP, a potent caspase inhibitor, is highly expressed in acute myeloid leukemia (AML) cells and contributes to chemoresistance. A multi-center phase 1/2 trial of XIAP antisense oligonucleotide AEG35156 in combination with idarubicin/cytarabine was conducted in 56 patients with relapsed/refractory AML. Herein we report the pharmacodynamic studies of the patients enrolled at M. D. Anderson Cancer Center. A total of 13 patients were enrolled in our institution: five in phase 1 (12-350 mg/m² AEG35156) and eight in phase 2 (350 mg/m² AEG35156) of the protocol. AEG35156 was administered on 3 consecutive days and then weekly up to a maximum of 35 days. Blood samples were collected from patients on days 1 through 5 and on day 28-35 post-chemotherapy for detection of XIAP levels and apoptosis. AEG35156 treatment led to dose-dependent decreases of XIAP mRNA levels (42-100% reduction in phase 2 patients). XIAP protein levels were reduced in all five samples measured. Apoptosis induction was detected in 1/4 phase 1 and 4/5 phase 2 patients. Importantly, apoptosis was most pronounced in CD34+38- AML stem cells and all phase 2 patients showing apoptosis induction in CD34+38- cells achieved response. We conclude that at 350 mg/m², AEG35156 is effective in knocking down XIAP in circulating blasts accompanied by the preferential induction of apoptosis in CD34+38- AML stem cells.
XIAP 是一种强效的半胱氨酸天冬氨酸蛋白酶抑制剂，在急性髓系白血病 (AML) 细胞中高度表达，并有助于耐药性的产生。一项针对 XIAP 反义寡核苷酸 AEG35156 联合柔红霉素/阿糖胞苷治疗复发性/难治性 AML 的多中心 1/2 期试验在 56 例患者中进行。在此，我们报告了在 M. D. 安德森癌症中心入组患者的药效学研究结果。我们机构共入组 13 例患者：5 例入组方案的 1 期（12-350mg/m² AEG35156），8 例入组 2 期（350mg/m² AEG35156）。AEG35156 连续 3 天给药，然后每周给药，最多 35 天。在化疗后第 1 天至第 5 天和第 28-35 天采集患者的血样，以检测 XIAP 水平和细胞凋亡。AEG35156 治疗导致 XIAP mRNA 水平呈剂量依赖性下降（2 期患者的减少幅度为 42%-100%）。所有 5 个测量的样本中均检测到 XIAP 蛋白水平降低。在 1/4 例 1 期患者和 4/5 例 2 期患者中检测到凋亡诱导。重要的是，凋亡在 CD34+38-AML 干细胞中最为明显，所有显示 CD34+38-细胞中诱导凋亡的 2 期患者均有反应。我们得出结论，在 350mg/m²时，AEG35156 可有效降低循环性白血病细胞中的 XIAP，并伴随着 CD34+38-AML 干细胞中优先诱导凋亡。
