Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.
Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.
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DOI：
10.18632/oncotarget.15823
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发表时间：
2017-05-30
期刊：
影响因子：
--
通讯作者：
Hoffman RM
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作者：
Murakami T;Li S;Han Q;Tan Y;Kiyuna T;Igarashi K;Kawaguchi K;Hwang HK;Miyake K;Singh AS;Nelson SD;Dry SM;Li Y;Hiroshima Y;Lwin TM;DeLong JC;Chishima T;Tanaka K;Bouvet M;Endo I;Eilber FC;Hoffman RM
甲硫氨酸依赖是由于过度使用甲硫氨酸在癌症中发生异常的甲基转移反应。甲硫氨酸依赖可能是癌症中唯一的一般代谢缺陷。为了利用蛋氨酸依赖性进行治疗，我们实验室先前克隆了L-蛋氨酸α-脱氨基-γ-巯基甲烷裂解酶[EC 4.4.1.11]）。克隆的甲硫氨酸酶，称为重组甲硫氨酸酶，或rMET酶，已在人类癌细胞系的小鼠模型中进行了测试。尤文氏肉瘤是一种难治性疾病，尽管多模式治疗的发展改善了患者的预后。在此，我们报告了rMETase在患者来源的原位异种移植（PDOX）模型中对尤文肉瘤的疗效。将尤文肉瘤移植于裸鼠右胸壁建立PDOX模型。将8只尤文肉瘤PDOX小鼠随机分为未治疗对照组（n = 4）和rMETase治疗组（n = 4）。腹膜内（i. p.）每24小时一次连续14天在第15天，最后一次rMETase给药后24小时处死所有小鼠。与未处理的对照相比，rMETase有效地减少了肿瘤生长。在rMETase组中，来自超声处理的肿瘤的血浆和上清液的甲硫氨酸水平均较低。在任何时间点，两组之间的体重均无显著差异。本研究是第一个证明rMETase在PDOX模型中的功效，表明潜在的临床开发，特别是在恶性肿瘤如尤文氏肉瘤中。
Methionine dependence is due to the overuse of methionine for aberrant transmethylation reactions in cancer. Methionine dependence may be the only general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino-γ-mercaptomethane lyase [EC 4.4.1.11]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer cell lines. Ewing's sarcoma is recalcitrant disease even though development of multimodal therapy has improved patients'outcome. Here we report efficacy of rMETase against Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma was implanted in the right chest wall of nude mice to establish a PDOX model. Eight Ewing's sarcoma PDOX mice were randomized into untreated control group (n = 4) and rMETase treatment group (n = 4). rMETase (100 units) was injected intraperitoneally (i.p.) every 24 hours for 14 consecutive days. All mice were sacrificed on day-15, 24 hours after the last rMETase administration. rMETase effectively reduced tumor growth compared to untreated control. The methionine level both of plasma and supernatants derived from sonicated tumors was lower in the rMETase group. Body weight did not significantly differ at any time points between the 2 groups. The present study is the first demonstrating rMETase efficacy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as Ewing's sarcoma.