Improving Survival Rates in Two Models of Spontaneous Postoperative Metastasis in Mice by Combined Administration of a β-Adrenergic Antagonist and a Cyclooxygenase-2 Inhibitor
Improving Survival Rates in Two Models of Spontaneous Postoperative Metastasis in Mice by Combined Administration of a β-Adrenergic Antagonist and a Cyclooxygenase-2 Inhibitor
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DOI：
10.4049/jimmunol.0903301
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发表时间：
2010-03-01
影响因子：
4.4
通讯作者：
Ben-Eliyahu, Shamgar
中科院分区：
文献类型：
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作者：
Glasner, Ariella;Avraham, Roi;Ben-Eliyahu, Shamgar
临床实践不认为围手术期旁分泌和神经内分泌应激反应是癌症复发的危险因素，尽管最近的动物研究提供了支持性证据。可能的机制包括应激激素对肿瘤细胞和宿主生理的影响。在本研究中，我们在原发肿瘤切除的小鼠中测试了围手术期阻断儿茶酚胺和前列腺素的生存增强潜力，并研究了可能的介导机制。C57BL/6J小鼠脚掌内接种同基因b16f10.9黑色素瘤或Lewis肺癌，当肿瘤发展超过100 μ l时，截肢。截肢前给予临床使用的β -肾上腺素能拮抗剂普萘洛尔和/或环氧化酶-2抑制剂乙度酸一次，监测无复发生存期。在不同的研究中，研究了NK细胞毒性、白细胞分子功能标志物和肿瘤细胞分泌血管内皮生长因子在手术和药物治疗中的作用。结果表明，心得安和依托度酸联合用药，而不是单独用药，显著提高了两种肿瘤模型的生存率，并且与已建立的免疫刺激剂（IL-12和多肌酸-多胞酸）一样有效。手术显著降低NK细胞毒性和NK细胞Fas配体和CD11a的表达，降低所有循环淋巴细胞亚型浓度，增加皮质酮水平。心得安和依托度酸可以抵消这些干扰。B16和3LL在体外分泌血管内皮生长因子，但分泌不受儿茶酚胺激动剂、前列腺素、皮质酮、心得安或依托度酸的影响。总的来说，普萘洛尔和依托度酸可以在大多数癌症患者围手术期应用，风险最小，成本低，已经抵消了一些免疫和内分泌紊乱，提高了原发肿瘤切除小鼠的无复发生存率。免疫学杂志，2010,(4):2449-2457。
Clinical practice does not consider perioperative paracrine and neuroendocrine stress responses as risk factors for cancer recurrence, although recent animal studies provided supportive evidence. Suggested mechanisms include the effects of stress-hormones on tumor cells and on host physiology. In this study, in mice undergoing primary tumor excision, we tested the survival-enhancing potential of perioperative blockade of catecholamines and prostaglandins, and studied potential mediating mechanisms. C57BL/6J mice were inoculated intrafootpad with syngeneic B16F10.9-melanoma or Lewis lung carcinoma, and the paw was amputated when a developing tumor exceeded 100 mu l. The clinically used beta-adrenergic antagonist propranolol, and/or the cyclooxygenase-2 inhibitor etodolac, were administered once before amputation, and recurrence-free survival was monitored. In different studies, NK cytotoxicity, leukocytes' molecular functional markers, and vascular endothelial growth factor secretion by tumor cells were studied in the context of surgery and drug treatments. The findings indicated that the combination of propranolol and etodolac, but neither drug alone, significantly and markedly improved survival rates in both tumor models, and was as effective as established immunostimulatory agents (IL-12 and polyinosinic-polycytiylic acid). Surgery markedly reduced NK cytotoxicity and NK cell expression of Fas ligand and CD11a, reduced all circulating lymphocyte-subtype concentrations, and increased corticosterone levels. Propranolol and etodolac administration counteracted these perturbations. B16 and 3LL secreted vascular endothelial growth factor in vitro, but secretion was not affected by catecholamine agonists, prostaglandins, corticosterone, propranolol, or etodolac. Overall, propranolol and etodolac administration, which could be applied perioperatively in most cancer patients with minimal risk and low cost, has counteracted several immunologic and endocrinologic perturbations and improved recurrence-free survival rates in mice undergoing primary tumor excision. The Journal of Immunology, 2010,184: 2449-2457.