文章：

CD123靶向溶瘤腺病毒体外和体内抑制急性髓系白血病细胞增殖的实验研究

CD123 targeting oncolytic adenoviruses suppress acute myeloid leukemia cell proliferation in vitro and in vivo

原文发布日期：2014-03-21

DOI: 10.1038/bcj.2014.15

类型: Original Article

开放获取: 是

英文摘要：

We report here a novel strategy to redirect oncolytic adenoviruses to CD123 by carry a soluble coxsackie-adenovirus receptor (sCAR)-IL3 expression cassette in the viral genome to form Ad.IL3, which sustainably infected acute myeloid leukemia (AML) cells through CD123. Ad.IL3 was further engineered to harbor gene encoding manganese superoxide dismutase (MnSOD) or mannose-binding plant lectin Pinellia pedatisecta agglutinin (PPA), forming Ad.IL3-MnSOD and Ad.IL3-PPA. As compared with Ad.IL3 or Ad.sp-E1A control, Ad.IL3-MnSOD and Ad.IL3-PPA significantly suppressed in vitro proliferation of HL60 and KG-1 cells. Elevated apoptosis was detected in HL60 and KG-1 cells treated with either Ad.IL3-MnSOD or Ad.IL3-PPA. The caspase-9–caspase-7 pathway was determined to be activated by Ad.IL3-MnSOD as well as by Ad.IL3-PPA in HL60 cells. In an HL60/Luc xenograft nonobese diabetic/severe-combined immunodeficiency mice model, Ad.IL3-MnSOD and Ad.IL3-PPA suppressed cancer cell growth as compared with Ad.IL3. A significant difference of cancer cell burden was detected between Ad.IL3 and Ad.IL3-PPA groups at day 9 after treatment. Furthermore, Ad.IL3-MnSOD significantly prolonged mouse survival as compared with Ad.sp-E1A. These findings demonstrated that Ad.IL3-gene could serve as a novel agent for AML therapy. Harboring sCAR-ligand expression cassette in the viral genome may provide a universal method to redirect oncolytic adenoviruses to various membrane receptors on cancer cells resisting serotype 5 adenovirus infection.

摘要翻译： 

我们在此报告一种新型策略，通过在水瘤性腺病毒基因组中携带可溶性柯萨奇-腺病毒受体（sCAR）-IL3表达盒，形成Ad.IL3，从而将病毒重定向至CD123，实现通过CD123持续感染急性髓系白血病（AML）细胞。进一步对Ad.IL3进行改造，使其携带编码锰超氧化物歧化酶（MnSOD）或植物凝集素半夏凝集素（PPA）的基因，形成Ad.IL3-MnSOD和Ad.IL3-PPA。与Ad.IL3或Ad.sp-E1A对照相比，Ad.IL3-MnSOD和Ad.IL3-PPA在体外显著抑制HL60和KG-1细胞的增殖。经Ad.IL3-MnSOD或Ad.IL3-PPA处理的HL60和KG-1细胞中检测到凋亡增加。在HL60细胞中，Ad.IL3-MnSOD和Ad.IL3-PPA均激活了caspase-9–caspase-7通路。在HL60/Luc移植的非肥胖糖尿病/重症联合免疫缺陷小鼠模型中，与Ad.IL3相比，Ad.IL3-MnSOD和Ad.IL3-PPA抑制了癌细胞生长。治疗后第9天，Ad.IL3组与Ad.IL3-PPA组之间的癌细胞负荷存在显著差异。此外，与Ad.sp-E1A相比，Ad.IL3-MnSOD显著延长了小鼠存活时间。这些发现表明Ad.IL3基因可作为AML治疗的新型制剂。在病毒基因组中携带sCAR-配体表达盒可能为重定向水瘤性腺病毒至抵抗5型腺病毒感染的癌细胞表面多种膜受体提供通用方法。

原文链接：

CD123 targeting oncolytic adenoviruses suppress acute myeloid leukemia cell proliferation in vitro and in vivo