Serial monitoring of human systemic and xenograft models of leukemia using a novel vascular disrupting agent.
Serial monitoring of human systemic and xenograft models of leukemia using a novel vascular disrupting agent.
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DOI：
10.1038/leu.2012.48
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发表时间：
2012-08
期刊：
影响因子：
11.4
通讯作者：
Bradbury MS
中科院分区：
文献类型：
--
作者：
Benezra M;Phillips E;Tilki D;Ding BS;Butler J;Dobrenkov K;Siim B;Chaplin D;Rafii S;Rabbany S;Bradbury MS
急性白血病治疗的进展已导致缓解率显著提高，尽管疾病复发构成显著风险。通过利用敏感的、非侵入性的成像引导，可以加速检测早期白血病浸润和靶向治疗后残留肿瘤负荷的程度，从而实现更有效的治疗计划。我们使用报告基因成像技术和小鼠全身给予luc+和GFP+人白血病细胞（LC），证明了新一代血管破坏剂考布他汀-A1-二磷酸盐（OXi 4503）的显著生存益处和治疗功效。在治疗前，连续监测双转导细胞的归巢，并使用生物发光成像（BLI）绘制全身细胞分布。成像结果与实体器官/组织中的定量GFP表达水平密切相关，表明测量的BLI信号提供了系统性白血病模型中肿瘤组织负荷的高度灵敏和可靠的生物标志物。因此，这种光学技术可以作为强大的非侵入性成像工具，用于临床前药物发现和快速筛选有前途的治疗剂，以建立效力，治疗功效和生存优势。我们进一步表明，GFP+ HL-60细胞居住在非常接近VE-钙粘蛋白和CD 31-表达内皮细胞，这表明血管周围的小生境可能有一个关键的作用，在维护和生存的LC。
Advances in the treatment of acute leukemia have resulted in significantly improved remission rates, although disease relapse poses a significant risk. By utilizing sensitive, non-invasive imaging guidance, detection of early leukemic infiltration and the extent of residual tumor burden after targeted therapy can be expedited, leading to more efficient treatment planning. We demonstrated marked survival benefit and therapeutic efficacy of a new-generation vascular disrupting agent, combretastatin-A1-diphosphate (OXi4503), using reporter gene-imaging technologies and mice systemically administered luc+ and GFP+ human leukemic cells (LCs). Before treatment, homing of double-transduced cells was serially monitored and whole-body cellular distributions were mapped using bioluminescence imaging (BLI). Imaging findings strongly correlated with quantitative GFP expression levels in solid organs/tissues, suggesting that the measured BLI signal provides a highly sensitive and reliable biomarker of tumor tissue burden in systemic leukemic models. Such optical technologies can thereby serve as robust non-invasive imaging tools for preclinical drug discovery and for rapidly screening promising therapeutic agents to establish potency, treatment efficacy and survival advantage. We further show that GFP+ HL-60 cells reside in close proximity to VE-cadherin- and CD31-expressing endothelial cells, suggesting that the perivascular niche may have a critical role in the maintenance and survival of LCs.