Disulfiram reduces metastatic osteosarcoma tumor burden in an immunocompetent Balb/c or-thotopic mouse model.
Disulfiram reduces metastatic osteosarcoma tumor burden in an immunocompetent Balb/c or-thotopic mouse model.
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DOI：
10.18632/oncotarget.25733
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发表时间：
2018-07-10
期刊：
影响因子：
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通讯作者：
Weiss KR
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作者：
Crasto JA;Fourman MS;Morales-Restrepo A;Mahjoub A;Mandell JB;Ramnath K;Tebbets JC;Watters RJ;Weiss KR
几十年来，骨肉瘤（OS）和肺转移患者的总生存率一直停滞在15-30%。双硫仑（DSF）是FDA批准的醛脱氢酶抑制剂，可在体外降低OS细胞的转移表型。在这里，我们评估其在体内的疗效，相比阿霉素化疗，在先前验证的转移性OS的原位模型。所有治疗组显示出显着减少定量OS转移负荷与对照组相比。Lo DSF处理动物的转移负荷与DXR组相当。95%的对照动物显示出转移性疾病的证据，这显著高于所有治疗组。与对照组相比，双硫仑治疗导致OS转移性疾病负担降低。这与多柔比星在药理学上等效。这两种疗法之间没有观察到累加效应。120只免疫活性Balb/c小鼠接受近端胫骨侧骺端注射5 × 105个K7 M2鼠OS细胞。注射后三周开始治疗：生理盐水（对照）、低剂量双硫仑（Lo DSF）、高剂量双硫仑（Hi DSF）、多柔比星（DXR）、Lo DSF + DXR和Hi DSF + DXR。在4周时进行经股动脉截肢。采用近红外吲哚菁绿色（ICG）血管造影术定量测定转移性肿瘤负荷。
The overall survival rate of patients with osteosarcoma (OS) and pulmonary metastases has remained stagnant at 15–30% for several decades. Disulfiram (DSF) is an FDA-approved aldehyde dehydrogenase inhibitor that reduces the metastatic phenotype of OS cells in vitro. Here we evaluate its in vivo efficacy, as compared to doxorubicin chemotherapy, in a previously-validated orthotopic model of metastatic OS. All treatment groups displayed a significantly reduced quantitative OS metastatic burden compared with controls. The metastatic burden of Lo DSF-treated animals was equivalent to the DXR group. Ninety-five percent of control animals displayed evidence of metastatic disease, which was significantly greater than all treatment groups. Disulfiram treatment resulted in a reduced burden of OS metastatic disease compared with controls. This was statistically-equivalent to doxorubicin. No additive effect was observed between these two therapies. One-hundred twenty immunocompetent Balb/c mice received proximal tibia paraphyseal injections of 5 × 105 K7M2 murine OS cells. Therapy began three weeks after injection: saline (control), low-dose disulfiram (Lo DSF), high-dose disulfiram (Hi DSF), doxorubicin (DXR), Lo DSF + DXR, and Hi DSF + DXR. Transfemoral amputations were performed at 4 weeks. Quantitative metastatic tumor burden was measured using near-infrared indocyanine green (ICG) angiography.