Recombinant methioninase in combination with doxorubicin (DOX) overcomes first-line DOX resistance in a patient-derived orthotopic xenograft nude-mouse model of undifferentiated spindle-cell sarcoma
Recombinant methioninase in combination with doxorubicin (DOX) overcomes first-line DOX resistance in a patient-derived orthotopic xenograft nude-mouse model of undifferentiated spindle-cell sarcoma
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DOI：
10.1016/j.canlet.2017.12.028
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发表时间：
2018-03-28
期刊：
影响因子：
9.7
通讯作者：
Hoffman, Robert M.
中科院分区：
文献类型：
--
作者：
Igarashi, Kentaro;Kawaguchi, Kei;Hoffman, Robert M.
我们以前建立了一个未分化梭形细胞肉瘤（USCS）的患者源性原位异种移植（PDOX）模型。重组甲硫氨酸酶（rMETase）先前已在人类癌症的PDOX小鼠模型中证明了疗效。在本研究中，我们确定了rMETase与多柔比星（DOX）的组合是否可以克服USCS的PDOX模型中的一线DOX耐药性。当肿瘤体积达到100 mm 3时，将USCS PDOX小鼠模型随机分为以下组（3）：G1，未处理的对照; G2，多柔比星（DOX）（3 mg/kg，腹膜内[i. p.]注射，每周，持续2周）; G3，rMETase（100单位/小鼠，i. p.，每天，持续2周）; G4，DOX（3 mg/kg，i. p.，每周，持续2周）与rMETase（100单位/小鼠，i. p.，每日一次，持续2周）。每周两次测量肿瘤大小和体重。在启动后第14天，USCS PDOX肿瘤大小为（G1）：360 +/- 85 mm（3）; DOX（G2）：355 +/- 111 mm（3），p=.927; rMETase（G3）：182 +/- 57 mm（3），p=.0003; DOX rMETase（G4）：134 +/- 29 mm（3），p=.00001。这些结果表明，rMETase可以克服USCS对DOX的抗性，这是该疾病的一线治疗。任何组中给药小鼠的体重均无显著差异。目前的结果证明了PDOX模型鉴定用于难治性癌症的有效疗法的能力和rMETase克服DOX抗性的潜力。由爱思唯尔公司出版
We have previously established a patient-derived orthotopic xenograft (PDOX) model of undifferentiated spindle cell sarcoma (USCS). Recombinant methioninase (rMETase) has previously demonstrated efficacy in PDOX mouse models of human cancers. In the present study, we determined if rMETase in combination with doxorubicin (DOX) can overcome first-line DOX resistance in a PDOX models of USCS. The USCS PDOX mouse models were randomized into the following groups when tumor volume reached 100 mm(3): G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks); G3, rMETase (100 units/mouse, i.p., daily, for 2 weeks); G4, DOX (3 mg/kg, i.p., weekly, for 2 weeks) combined with rMETase (100 units/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured twice a week. On day 14 after initiation, the USCS PDOX tumor sizes were (G1): 360 +/- 85 mm(3); DOX (G2): 355 +/- 111 mm(3), p=.927; rMETase (G3): 182 +/- 57 mm(3), p=.0003; DOX rMETase (G4): 134 +/- 29 mm(3), p=.00001. These results indicate that rMETase can overcome USCS resistance to DOX, which is first line therapy for this disease. The body weight of treated mice was not significantly different in any group. The present results demonstrate the power of the PDOX model to identify effective therapy for recalcitrant cancer and the potential of rMETase to overcome DOX resistance. Published by Elsevier B.V.