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联合内质网应激诱导剂硼替佐米和维甲酸作为转移性黑色素瘤的一种新型治疗策略。

Combining the endoplasmic reticulum stress-inducing agents bortezomib and fenretinide as a novel therapeutic strategy for metastatic melanoma.

作者信息

Hill David S, Martin Shaun, Armstrong Jane L, Flockhart Ross, Tonison Joge J, Simpson Dominic G, Birch-Machin Mark A, Redfern Christopher P F, Lovat Penny E

机构信息

Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, United Kingdom.

出版信息

Clin Cancer Res. 2009 Feb 15;15(4):1192-8. doi: 10.1158/1078-0432.CCR-08-2150.

Abstract

PURPOSE

Single-agent chemotherapy is largely the treatment of choice for systemic therapy of metastatic melanoma, but survival rates are low, and novel adjuvant and systemic therapies are urgently required. Endoplasmic reticulum (ER) stress is a potential therapeutic target, and two relatively new drugs, fenretinide and bortezomib (Velcade), each acting via different cellular mechanisms, induce ER stress leading to apoptosis in melanoma cells. The aim of this study was to test the hypothesis that apoptosis of melanoma cells may be increased by combining clinically achievable concentrations of fenretinide and bortezomib.

EXPERIMENTAL DESIGN

Three human melanoma cell lines were used to assess changes in viability and the induction of apoptosis in response to fenretinide, bortezomib, or both drugs together. A s.c. xenograft model was used to test responses in vivo.

RESULTS

Fenretinide and bortezomib synergistically decreased viability and increased apoptosis in all three melanoma lines at clinically achievable concentrations. This was also reflected by increased expression of GADD153, a marker of ER stress-induced apoptosis. In vivo, fenretinide in combination with bortezomib gave a marked reduction in xenograft tumor volume and an increase in apoptosis compared with fenretinide or bortezomib alone. The cell cycle stage of tumor cells in vivo were similar to that predicted from the effects of each drug or the combination in vitro.

CONCLUSIONS

These results suggest that fenretinide and bortezomib, both of which are available in clinical formulation, warrant clinical evaluation as a combination therapy for metastatic melanoma.

摘要

目的

单药化疗在很大程度上是转移性黑色素瘤全身治疗的首选方法,但生存率较低,因此迫切需要新的辅助治疗和全身治疗方法。内质网(ER)应激是一个潜在的治疗靶点,两种相对较新的药物,维甲酸和硼替佐米(万珂),通过不同的细胞机制发挥作用,可诱导ER应激,导致黑色素瘤细胞凋亡。本研究的目的是检验以下假设:联合使用临床可达到浓度的维甲酸和硼替佐米可能会增加黑色素瘤细胞的凋亡。

实验设计

使用三种人类黑色素瘤细胞系来评估维甲酸、硼替佐米或两种药物联合使用时细胞活力的变化以及凋亡的诱导情况。采用皮下异种移植模型来测试体内反应。

结果

在临床可达到的浓度下,维甲酸和硼替佐米协同降低了所有三种黑色素瘤细胞系的活力并增加了凋亡。这也反映在内质网应激诱导凋亡的标志物GADD153表达增加上。在体内,与单独使用维甲酸或硼替佐米相比,维甲酸联合硼替佐米可使异种移植瘤体积显著减小,并使凋亡增加。体内肿瘤细胞的细胞周期阶段与每种药物或联合用药在体外的作用所预测的相似。

结论

这些结果表明,临床制剂中已有的维甲酸和硼替佐米,作为转移性黑色素瘤的联合治疗方法值得进行临床评估。

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