Terry Fox Laboratory, British Columbia Cancer Agency and Department of Medicine, University of British Columbia, 675 West 10 Ave., Vancouver, BC, V5Z 1L3 Canada.
Leuk Res. 2010 Aug;34(8):1035-42. doi: 10.1016/j.leukres.2009.12.008.
Despite initial remissions, most patients with Ph chromosome positive (Ph(+)) acute leukemia (AL) become refractory to tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib. This study was designed to determine if targeting the interleukin-3 receptor (IL-3R) with a diphtheria toxin fusion protein (DT(388)IL3) would improve the effectiveness of TKIs against Ph(+) AL cells. IL-3R subunits were detected on most Ph(+) cells and the IC50 for killing of colony forming cell (CFC) with DT(388)IL3 correlated with the level of IL-3Ralpha subunit by FACS. DT(388)IL3 synergized with both imatinib and dasatinib for killing of malignant CFCs. Long-term suspension culture-initiating cells (SC-ICs) and quiescent leukemic cells (G(0) in cell cycle) also were studied and synergistic interactions were again demonstrated. Thus, cotreatment with TKIs and DT(388)IL3 is much more effective in eliminating Ph(+) leukemic progenitors that express IL-3R than either agent alone.
尽管最初有缓解，但大多数 Ph 染色体阳性（Ph(+））急性白血病（AL）患者对酪氨酸激酶抑制剂（TKI）如伊马替尼和达沙替尼产生耐药性。本研究旨在确定使用白喉毒素融合蛋白（DT(388)IL3）靶向白细胞介素-3 受体（IL-3R）是否会提高 TKI 对 Ph(+) AL 细胞的有效性。IL-3R 亚基在大多数 Ph(+)细胞上都有检测到，并且 DT(388)IL3 杀死集落形成细胞（CFC）的 IC50 与 FACS 检测到的 IL-3Ralpha 亚基水平相关。DT(388)IL3 与伊马替尼和达沙替尼协同作用，均可杀死恶性 CFC。还研究了长期悬浮培养起始细胞（SC-IC）和静止白血病细胞（细胞周期中的 G(0)），并再次证明了协同作用。因此，与单独使用任何一种药物相比，TKI 和 DT(388)IL3 的联合治疗更有效地消除表达 IL-3R 的 Ph(+)白血病祖细胞。
