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.