The combination of temozolomide-irinotecan regresses a doxorubicin-resistant patient-derived orthotopic xenograft (PDOX) nude-mouse model of recurrent Ewing's sarcoma with a FUS-ERG fusion and CDKN2A deletion: Direction for third-line patient therapy.
The combination of temozolomide-irinotecan regresses a doxorubicin-resistant patient-derived orthotopic xenograft (PDOX) nude-mouse model of recurrent Ewing's sarcoma with a FUS-ERG fusion and CDKN2A deletion: Direction for third-line patient therapy.
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DOI：
10.18632/oncotarget.20789
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发表时间：
2017-11-28
期刊：
影响因子：
--
通讯作者：
Hoffman RM
中科院分区：
文献类型：
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作者：
Miyake K;Murakami T;Kiyuna T;Igarashi K;Kawaguchi K;Miyake M;Li Y;Nelson SD;Dry SM;Bouvet M;Elliott IA;Russell TA;Singh AS;Eckardt MA;Hiroshima Y;Momiyama M;Matsuyama R;Chishima T;Endo I;Eilber FC;Hoffman RM
本研究的目的是确定多柔比星耐药转移性尤文肉瘤的患者来源的原位异种移植（PDOX）裸鼠模型的有用性，该模型具有FUS-ERG融合和CDKN 2A缺失的独特组合，以确定用于患者三线化疗的有效药物。我们以前的研究表明，细胞周期蛋白依赖性激酶4/6（CDK 4/6）和胰岛素样生长因子-1受体（IGF-1 R）抑制剂对尤文肉瘤PDOX有效，但对阿霉素无效，类似于患者对阿霉素的耐药性。既往PDOX研究的结果成功用于患者的二线治疗。在本研究中，当肿瘤体积达到60 mm 3时，将在右胸壁中建立有尤文氏肉瘤的PDOX小鼠随机分为5组：未处理对照;吉西他滨与多西他赛组合（腹膜内[i. p.]注射，每周，持续2周）;伊立替康与替莫唑胺组合（伊立替康：腹膜内注射;替莫唑胺：口服施用，每日，持续2周）;帕唑帕尼（口服施用，每日，持续2周）; yondelis（静脉内注射，每周，持续2周）。在第15天处死所有小鼠。每周评估2次体重和肿瘤体积。处死后测量肿瘤重量。与未治疗对照组相比，伊立替康联合替莫唑胺是最有效的方案（p=0.022）。吉西他滨联合多西他赛也有效（p=0.026）。与未处理的对照相比，帕唑帕尼和yondelis没有显著功效（p=0.130，p=0.818）。这些结果可以在医生要求后两个月内获得，并用于患者的三线治疗。
The aim of the present study was to determine the usefulness of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of a doxorubicin-resistant metastatic Ewing’s sarcoma, with a unique combination of a FUS-ERG fusion and CDKN2A deletion, to identify effective drugs for third-line chemotherapy of the patient. Our previous study showed that cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors were effective on the Ewing’s sarcoma PDOX, but not doxorubicin, similar to the patient’s resistance to doxorubicin. The results of the previous PDOX study were successfully used for second-line therapy of the patiend. In the present study, the PDOX mice established with the Ewing’s sarcoma in the right chest wall were randomized into 5 groups when the tumor volume reached 60 mm3: untreated control; gemcitabine combined with docetaxel (intraperitoneal [i.p.] injection, weekly, for 2 weeks); irinotecan combined with temozolomide (irinotecan: i.p. injection; temozolomide: oral administration, daily, for 2 weeks); pazopanib (oral administration, daily, for 2 weeks); yondelis (intravenous injection, weekly, for 2 weeks). All mice were sacrificed on day 15. Body weight and tumor volume were assessed 2 times per week. Tumor weight was measured after sacrifice. Irinotecan combined with temozolomide was the most effective regimen compared to the untreated control group (p=0.022). Gemcitabine combined with docetaxel was also effective (p=0.026). Pazopanib and yondelis did not have significant efficacy compared to the untreated control (p=0.130, p=0.818). These results could be obtained within two months after the physician’s request and were used for third-line therapy of the patient.