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
| Autor: | Ella Rosenne, Roi Avraham, Oded Zmora, Shaily Shemer, Hadas Meiboom, Shamgar Ben-Eliyahu, Marganit Benish, Ariella Glasner |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Male
medicine.medical_specialty Fas Ligand Protein Adrenergic beta-Antagonists Immunology Melanoma Experimental Propranolol Amputation Surgical Metastasis Carcinoma Lewis Lung Mice chemistry.chemical_compound Postoperative Complications Cell Line Tumor Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Animals Immunology and Allergy CD11a Antigen Neoplasm Metastasis Etodolac Survival rate Laparotomy Cyclooxygenase 2 Inhibitors biology business.industry Lewis lung carcinoma medicine.disease Interleukin-12 Primary tumor Killer Cells Natural Mice Inbred C57BL Survival Rate Vascular endothelial growth factor Poly I-C Endocrinology chemistry biology.protein Female Cyclooxygenase business medicine.drug |
| Zdroj: | The Journal of Immunology. 184:2449-2457 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.0903301 |
| Popis: | 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 μl. The clinically used β-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. |
| Databáze: | OpenAIRE |
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