Department of Medicine, Roswell Park Cancer Institute, and SUNY-UB, Buffalo, New York, USA.
Mol Cancer Ther. 2010 Oct;9(10):2737-51. doi: 10.1158/1535-7163.MCT-10-0334. Epub 2010 Oct 5.
We examined whether potent vascular endothelial growth factor (VEGF) blockade mediated by aflibercept, a decoy VEGF receptor (VEGFR) 1/2 moiety with stronger affinity for VEGF than bevacizumab, resulted in antileukemia effects and enhanced the efficacy of systemic chemotherapy. The efficacy of aflibercept alone and in combination with doxorubicin was evaluated in human VEGF-expressing acute myeloid leukemia (AML) cell lines and primary cells xenotransplanted into immunodeficient mice. Aflibercept reduced primary VEGF/VEGFR-positive AML colony formation growth in vitro and inhibited AML xenograft growth up to 93% in association with antiangiogenic and antiproliferative effects, hypoxia, and VEGF sequestration in multiple models. High VEGF-A expression by AML cells promoted in vivo xenograft growth and aflibercept sensitivity. Aflibercept therapy slowed disease progression in two systemic human AML xenograft models and reduced peripheral leukemia disease in a primary relapsed AML model in NOD/SCID/IL2Rγnull mice. Combination aflibercept and doxorubicin enhanced antitumor effects in local xenograft models. Sequential aflibercept followed by doxorubicin resulted in progressive anthracycline accumulation in marrow and extramedullary AML sites and resulted in 2-fold higher drug levels 24 hours after administration. In contrast, tissues (tumor, plasma, marrow) treated with chemotherapy only showed progressive drug clearance over time. Combination aflibercept and doxorubicin also resulted in vascular narrowing, decreased vessel number, and perivascular apoptosis. These data suggest that inefficient drug delivery by leukemia-associated vasculature may mediate chemoresistance and support further clinical evaluation of combination aflibercept and anthracycline therapy in refractory/relapsed AML patients.
我们研究了阿柏西普（一种与贝伐珠单抗相比对 VEGF 具有更强亲和力的诱饵 VEGFR1/2 部分）强效的血管内皮生长因子（VEGF）阻断作用是否会产生抗白血病作用，并增强全身化疗的疗效。在表达人 VEGF 的急性髓细胞白血病（AML）细胞系和异种移植到免疫缺陷小鼠的原代细胞中，评估了阿柏西普单独和联合多柔比星的疗效。阿柏西普可减少体外原代 VEGF/VEGFR 阳性 AML 集落形成生长，并在多种模型中通过抗血管生成和抗增殖作用、缺氧和 VEGF 隔离，抑制 AML 异种移植物生长达 93%。AML 细胞中高 VEGF-A 的表达促进了体内异种移植物的生长和阿柏西普的敏感性。阿柏西普治疗可减缓两种全身性人 AML 异种移植模型中的疾病进展，并减少 NOD/SCID/IL2Rγnull 小鼠原发性复发性 AML 模型中的外周白血病疾病。阿柏西普联合多柔比星增强了局部异种移植模型中的抗肿瘤作用。序贯阿柏西普联合多柔比星可导致骨髓和骨髓外 AML 部位的蒽环类药物积累逐渐增加，并在给药后 24 小时使药物水平增加 2 倍。相比之下，仅接受化疗治疗的组织（肿瘤、血浆、骨髓）随着时间的推移会逐渐清除药物。阿柏西普联合多柔比星还导致血管狭窄、血管数量减少和血管周围细胞凋亡。这些数据表明，白血病相关血管的药物递送效率低下可能介导化疗耐药，并支持进一步评估阿柏西普联合蒽环类药物治疗难治/复发性 AML 患者的临床疗效。
