Combination of sorafenib and everolimus impacts therapeutically on adrenocortical tumor models
Combination of sorafenib and everolimus impacts therapeutically on adrenocortical tumor models
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DOI：
10.1530/erc-11-0337
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发表时间：
2012-08-01
影响因子：
3.9
通讯作者：
Mantero, Franco
中科院分区：
文献类型：
--
作者：
Mariniello, Barbara;Rosato, Antonio;Mantero, Franco
肾上腺皮质癌(ACC)患者的治疗选择不足。基于酪氨酸激酶抑制剂索拉非尼和雷帕霉素哺乳动物靶点抑制剂伊洛莫司对不同组织类型肿瘤的疗效，我们的目标是在肾上腺皮质癌模型中测试这些药物。应用实时荧光定量聚合酶链式反应和免疫组织化学方法及免疫印迹技术，对18例肾上腺癌、33例醛固酮腺瘤、12例皮质醇腺瘤和6例正常肾上腺皮质中血管内皮生长因子及其受体(VEGFR1-2)在SW13和H295R癌细胞中的表达进行了研究。在原代培养的肾上腺皮质细胞和SW13、H295R细胞上，分别检测索拉非尼和伊维莫司单独或联合应用的效果，评价其对免疫缺陷小鼠异种移植瘤细胞的生长抑制作用。所有标本中均可检测到血管内皮生长因子和血管内皮生长因子受体1-2的表达，且在2/3的癌组织中呈过度表达。细胞活力呈剂量依赖性抑制，尤以SW13细胞为甚；联合用药对细胞生长有明显的协同抑制作用。在药物处理的肿瘤细胞中观察到了更多的凋亡，特别是索拉非尼。最后，在联合用药治疗的SW13异种移植模型中，观察到明显的质量减少和存活增加。我们的数据提示在ACC中可能存在一个自分泌的血管内皮生长因子环路。此外，分子靶向药物的组合可能具有抗血管生成和直接抗肿瘤的作用，因此可能成为治疗ACC的一种新的治疗工具。内分泌相关癌症(2012)19 527-539
Treatment options are insufficient in patients with adrenocortical carcinoma (ACC). Based on the efficacy of sorafenib, a tyrosine kinase inhibitor, and everolimus, an inhibitor of the mammalian target of rapamycin in tumors of different histotype, we aimed at testing these drugs in adrenocortical cancer models. The expression of vascular endothelial growth factor and its receptors (VEGFR1-2) was studied in 18 ACCs, 33 aldosterone-producing adenomas, 12 cortisol-producing adenomas, and six normal adrenal cortex by real-time PCR and immunohistochemistry and by immunoblotting in SW13 and H295R cancer cell lines. The effects of sorafenib and everolimus, alone or in combination, were tested on primary adrenocortical cultures and SW13 and H295R cells by evaluating cell viability and apoptosis in vitro and tumor growth inhibition of tumor cell line xenografts in immunodeficient mice in vivo. VEGF and VEGFR1-2 were detected in all samples and appeared over-expressed in two-thirds of ACC specimens. Dose-dependent inhibition of cell viability was observed particularly in SW13 cells after 24 h treatment with either drug; drug combination produced markedly synergistic growth inhibition. Increasing apoptosis was observed in tumor cells treated with the drugs, particularly with sorafenib. Finally, a significant mass reduction and increased survival were observed in SW13 xenograft model undergoing treatment with the drugs in combination. Our data suggest that an autocrine VEGF loop may exist within ACC. Furthermore, a combination of molecularly targeted agents may have both antiangiogenic and direct antitumor effects and thus could represent a new therapeutic tool for the treatment of ACC. Endocrine-Related Cancer (2012) 19 527-539