Neuroimmunology Research Unit, Department of Psychology, Tel Aviv University, Tel Aviv 69978, Israel.
J Immunol. 2010 Mar 1;184(5):2449-57. doi: 10.4049/jimmunol.0903301. Epub 2010 Feb 1.
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 microl. 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.
临床实践并未将围手术期旁分泌和神经内分泌应激反应视为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。提出的机制包括应激激素对肿瘤细胞和宿主生理学的影响。在这项研究中，我们在接受原发性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，并研究了潜在的介导机制。C57BL/6J 小鼠在足底接种同源 B16F10.9-黑色素瘤或 Lewis 肺腺癌，当发展中的肿瘤超过 100 微升时切除爪子。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 抑制剂依托度酸在截肢前单次给药，并监测无复发生存率。在不同的研究中，研究了手术和药物治疗背景下 NK 细胞毒性、白细胞分子功能标志物以及肿瘤细胞分泌的血管内皮生长因子。研究结果表明，普萘洛尔和依托度酸的联合使用，而不是单独使用任何一种药物，在两种肿瘤模型中均显著且明显地提高了生存率，并且与既定的免疫刺激剂（IL-12 和聚肌苷酸-聚胞苷酸）一样有效。手术显著降低了 NK 细胞毒性和 NK 细胞 Fas 配体和 CD11a 的表达，降低了所有循环淋巴细胞亚型的浓度，并增加了皮质酮水平。普萘洛尔和依托度酸的给药拮抗了这些干扰。B16 和 3LL 在体外分泌血管内皮生长因子，但儿茶酚胺激动剂、前列腺素、皮质酮、普萘洛尔或依托度酸对其分泌没有影响。总的来说，普萘洛尔和依托度酸的给药，在大多数癌症患者中可以在围手术期应用，风险最小，成本最低，它拮抗了几种免疫和内分泌干扰，并提高了接受原发性肿瘤切除的小鼠的无复发生存率。
