Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, CA, USA.
Department of Pediatrics, Stanford University, CA, USA.
Mol Oncol. 2019 Oct;13(10):2049-2061. doi: 10.1002/1878-0261.12556. Epub 2019 Aug 13.
The long-term survival of osteosarcoma patients with metastatic or recurrent disease remains dismal, and new therapeutic options are urgently needed. The purpose of our study was to compare the efficacy of CD47 mAb plus doxorubicin combination therapy in mouse models of osteosarcoma with CD47 mAb and doxorubicin monotherapy. Forty-eight NOD scid gamma (NSG) mice with intratibial MNNG/HOS tumors received CD47 mAb, doxorubicin, combination therapy, or control IgG treatment. Twenty-four mice (n = 6 per group) underwent pre- and post-treatment magnetic resonance imaging (MRI) scans with the macrophage marker ferumoxytol, bioluminescence imaging, and histological analysis. Tumor ferumoxytol enhancement, tumor flux, and tumor-associated macrophages (TAM) density were compared between different groups using a one-way ANOVA. Twenty-four additional NSG mice underwent survival analyses with Kaplan-Meier curves and a log-rank (Mantel-Cox) test. Intratibial osteosarcomas demonstrated significantly stronger ferumoxytol enhancement and significantly increased TAM quantities after CD47 mAb plus doxorubicin combination therapy compared to CD47 mAb (P = 0.02) and doxorubicin monotherapy (P = 0.001). Tumor-bearing mice treated with CD47 mAb plus doxorubicin combination therapy demonstrated significantly reduced tumor size and prolonged survival compared to control groups that received CD47 mAb (P = 0.03), doxorubicin monotherapy (P = 0.01), and control IgG (P = 0.001). In conclusion, CD47 mAb plus doxorubicin therapy demonstrates an additive therapeutic effect in mouse models of osteosarcomas, which can be monitored with an immediately clinically applicable MRI technique.
骨肉瘤患者转移性或复发性疾病的长期生存率仍然很差，迫切需要新的治疗选择。我们的研究目的是比较 CD47 mAb 联合多柔比星与 CD47 mAb 和多柔比星单药治疗在骨肉瘤小鼠模型中的疗效。48 只胫骨内 MNNG/HOS 肿瘤的 NOD scid gamma (NSG) 小鼠接受 CD47 mAb、多柔比星、联合治疗或对照 IgG 治疗。24 只小鼠（每组 6 只）在治疗前后接受巨噬细胞标志物 ferumoxytol、生物发光成像和组织学分析的磁共振成像 (MRI) 扫描。使用单向方差分析比较不同组之间的肿瘤 ferumoxytol 增强、肿瘤通量和肿瘤相关巨噬细胞 (TAM) 密度。另外 24 只 NSG 小鼠接受 Kaplan-Meier 曲线和对数秩 (Mantel-Cox) 检验的生存分析。与 CD47 mAb（P=0.02）和多柔比星单药治疗（P=0.001）相比，CD47 mAb 联合多柔比星治疗的胫骨内骨肉瘤显示出明显更强的 ferumoxytol 增强和明显增加的 TAM 数量。与接受 CD47 mAb（P=0.03）、多柔比星单药治疗（P=0.01）和对照 IgG（P=0.001）的对照组相比，接受 CD47 mAb 联合多柔比星治疗的荷瘤小鼠显示出肿瘤体积明显缩小和生存时间延长。总之，CD47 mAb 联合多柔比星治疗在骨肉瘤小鼠模型中表现出相加的治疗效果，可通过一种可立即临床应用的 MRI 技术进行监测。
