Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell 'don't eat me' signals off and 'eat me' signals on
Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell 'don't eat me' signals off and 'eat me' signals on
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DOI：
10.1002/1878-0261.12556
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发表时间：
2019-08-13
影响因子：
6.6
通讯作者：
Daldrup-Link, Heike E.
中科院分区：
文献类型：
--
作者：
Mohanty, Suchismita;Aghighi, Maryam;Daldrup-Link, Heike E.
患有转移性或复发性疾病的骨肉瘤患者的长期生存率仍然很低，迫切需要新的治疗选择。我们研究的目的是比较 CD47 mAb 加阿霉素联合治疗与 CD47 mAb 加阿霉素单药治疗在骨肉瘤小鼠模型中的疗效。 48 只患有胫骨内 MNNG/HOS 肿瘤的 NOD scid gamma (NSG) 小鼠接受 CD47 mAb、阿霉素、联合治疗或对照 IgG 治疗。 24 只小鼠（每组 n = 6）在治疗前和治疗后接受了巨噬细胞标记物 ferumoxytol 的磁共振成像 (MRI) 扫描、生物发光成像和组织学分析。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 小鼠接受了 Kaplan-Meier 曲线和对数秩 (Mantel-Cox) 检验的生存分析。与 CD47 mAb (P = 0.02) 和阿霉素单药治疗 (P = 0.001) 相比，CD47 mAb 加阿霉素联合治疗后，胫骨内骨肉瘤表现出明显更强的阿莫西托增强作用，并且 TAM 数量显着增加。与接受 CD47 mAb (P = 0.03)、阿霉素单一疗法 (P = 0.01) 和对照 IgG (P = 0.001) 的对照组相比，接受 CD47 mAb 加阿霉素联合疗法治疗的荷瘤小鼠的肿瘤大小显着减小，存活时间延长。总之，CD47 mAb 加阿霉素治疗在骨肉瘤小鼠模型中显示出附加治疗效果，可以通过立即应用于临床的 MRI 技术进行监测。
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.