Oral Recombinant Methioninase Combined with Caffeine and Doxorubicin Induced Regression of a Doxorubicin-resistant Synovial Sarcoma in a PDOX Mouse Model
Oral Recombinant Methioninase Combined with Caffeine and Doxorubicin Induced Regression of a Doxorubicin-resistant Synovial Sarcoma in a PDOX Mouse Model
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DOI：
10.21873/anticanres.12899
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发表时间：
2018-10-01
影响因子：
2
通讯作者：
Hoffman, Robert M.
中科院分区：
文献类型：
--
作者：
Higuchi, Takashi;Kawaguchi, Kei;Hoffman, Robert M.
背景/目的：滑膜肉瘤是一种化疗敏感性低的顽固性肿瘤。我们最近报道了重组蛋氨酸酶(RMETase)在患者来源的异种移植(PDOX)小鼠模型中抑制SS的生长，并且与一线药物阿霉素(DOX)联合使用时效果更好。咖啡因通过克服药物诱导的细胞周期停滞和增加随后的细胞凋亡来增强抗癌药物的疗效。在这里，我们确定了口服重组蛋氨酸酶(o-rMETase)联合咖啡因在SS-PDOX模型上的疗效。材料和方法：荷SS-PDOX荷瘤小鼠随机分为4组，每组6只：未治疗对照组、o-rMETase单独治疗组、o-rMETase加咖啡因治疗组、DOX+o-rMETase加咖啡因治疗组。治疗期间测量肿瘤大小和体重，治疗结束时测定血浆L蛋氨酸(MET)水平。结果：各剂量组均能显著抑制SS-PDOX肿瘤生长。咖啡因和o-rMETase联合应用比单独使用o-rMETase更有效。DOX联合o-rMETase和咖啡因可导致SS-PDOX的消退。O-rMETase治疗可降低血浆MET水平。结论：o-rMETase、咖啡因联合一线化疗治疗SS疗效显著，具有潜在的临床应用潜力。
Background/Aim: Synovial sarcoma (SS) is a recalcitrant neoplasm with low chemosensitivity. We recently reported that recombinant methioninase (rMETase) inhibited SS growth in a patient-derived orthotopic xenograft (PDOX) mouse model and was more effective when administered in combination with the first-line drug doxorubicin (DOX). Caffeine enhances the efficacy of anticancer drugs by overcoming drug-induced cell-cycle arrest and increasing subsequent apoptosis. Here, we determined the efficacy of oral recombinant methioninase (o-rMETase) in combined with caffeine on an SS-PDOX model. Materials and Methods: Mice bearing SS-PDOX tumors were randomized into four treatment groups of six: Untreated control; o-rMETase alone; o-rMETase with caffeine; DOX plus o-rMETase with caffeine. Tumor size and body weight were measured during the treatment and plasma L-methionine (MET) levels were measured at the end of treatment. Results: All treatments significantly inhibited SS-PDOX tumor growth. Combining caffeine with o-rMETase was more effective than o-rMETase alone. DOX combined with o-rMETase and caffeine led to regression of SS-PDOX. Plasma MET levels were reduced with o-rMETase treatment. Conclusion: These results suggest that combining o-rMETase and caffeine along with first-line chemotherapy can be highly effective for SS and has clinical potential for this recalcitrant disease.