Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor
Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor
复制标题
DOI：
10.1158/1078-0432.ccr-10-1354
复制
发表时间：
2010-10-01
影响因子：
11.5
通讯作者：
Ponzoni, Mirco
中科院分区：
文献类型：
--
作者：
Pastorino, Fabio;Loi, Monica;Ponzoni, Mirco
目的：神经母细胞瘤的治疗在不到一半的高危疾病患者中是成功的。在人神经母细胞瘤的临床前模型中，比较了水溶性聚乙二醇化SN38药物结合物EZN-2208和SN38的前体药物CPT-11的抗肿瘤活性。实验设计：通过对台盼蓝染色和Annexin V阳性细胞的计数来检测EZN-2208的体外细胞毒性，同时从存活、抗肿瘤和抗血管生成活性的角度来评价其治疗效果。结果：EZN-2208在体外通过诱导细胞凋亡/坏死和P53的表达，以及通过减少缺氧诱导因子(HIF)-1α/HIF-2α的表达，比CPT-11的作用增强约100倍。在神经母细胞瘤移植瘤中，EZN-2208的抗肿瘤作用优于CPT-11。EZN-2208治疗总是导致在试验结束时没有发现肿瘤，而CPT-11只观察到很小的疗效，通过荧光素酶测定或肿瘤大小评估，甚至通过用识别神经母细胞瘤细胞和细胞增殖的抗体对肿瘤组织切片进行染色来评估。在对阿霉素、顺铂、长春新碱、芬维替尼和拓扑替康耐药的神经母细胞瘤模型中，EZN-2208诱导了100%的治愈。它还可以阻止拓扑替康-长春新碱-阿霉素联合治疗后的肿瘤复发。机制实验显示，在EZN-2208治疗的小鼠肿瘤和移植于绒毛尿囊膜上的放射血管中，末端脱氧核苷酸转移酶介导的dUTP缺口末端标记和组蛋白H 2AX染色显著增强，血管内皮生长因子CD31、基质金属蛋白酶2和基质金属蛋白酶9的表达显著降低。结论：EZN-2208是一种最有前途的新型抗神经母细胞瘤药物。一项在儿科患者中进行的I期研究应该确定II期研究的最佳剂量。临床癌症资源；16(19)；4809-21。(C)2010年AACR。
Purpose: Treatment of neuroblastoma is successful in less than half of patients with high-risk disease. The antitumor activity of a water soluble pegylated SN38 drug conjugate, EZN-2208, was compared with CPT-11 (a prodrug for SN38) in preclinical models of human neuroblastoma.Experimental Design: The in vitro cytotoxicity of EZN-2208 was tested by counting trypan blue dye- and Annexin V-positive cells, whereas its therapeutic efficacy was evaluated, in terms of survival, and antitumor and antiangiogenic activities, in s.c. luciferase-transfected, pseudometastatic, and orthotopic neuroblastoma animal models.Results: EZN-2208 was about 100-fold more potent than CPT-11 in vitro, by inducing apoptosis/necrosis and p53 expression and by reducing hypoxia-inducible factor (HIF)-1 alpha/HIF-2 alpha expression. EZN-2208 gave superior antitumor effects compared with CPT-11 in neuroblastoma xenografts. EZN-2208 treatment always resulted in lack of tumor detection at the end of trials whereas only small therapeutic effects were observed with CPT-11, as assessed by luciferase assay or tumor size, or even by staining histologic sections of tumors with antibodies recognizing neuroblastoma cells and cell proliferation. In a neuroblastoma model resistant to doxorubicin, cisplatin, vincristine, fenretinide, and topotecan, EZN-2208 induced 100% curability. It also blocked tumor relapse after topotecan-vincristine-doxorubicin combined treatment. Mechanistic experiments showed statistically significantly enhanced terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Histone H2ax staining as well as decreased vascular endothelial growth factor, CD31, matrix metalloproteinase (MMP)-2, and MMP-9 expression in tumors removed from EZN-2208-treated mice and radiating vessels invading the tumor implanted onto the chorioallantoic membranes.Conclusions: EZN-2208 should be considered a most promising novel antineuroblastoma agent. An ongoing phase I study in pediatric patients should identify the optimal dose for a phase II study. Clin Cancer Res; 16(19); 4809-21. (C) 2010 AACR.