Background-COX inhibitors and β-blockers were recently suggested to reduce cancer

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.

In leukemia patients, stress and anxiety were suggested to predict poorer prognosis. Oncological patients experience ample physiological and psychological stress, potentially leading to increased secretion of stress factors, including epinephrine, corticosteroids, and prostaglandins. Here we tested whether environmental stress and these stress factors impact survival of leukemia-challenged rats, and studied mediating mechanisms. F344 rats were administered with a miniscule dose of 60 CRNK-16 leukemia cells, and were subjected to intermittent forced swim stress or to administration of physiologically relevant doses of epinephrine, prostaglandin-E2 or corticosterone. Stress and each stress factor, and/or their combinations, doubled mortality rates when acutely applied simultaneously with, or two or six days after tumor challenge. Acute administration of the β-adrenergic blocker nadolol diminished the effects of environmental stress, without affecting baseline survival rates. Prolonged β-adrenergic blockade or COX inhibition (using etodolac) also increased baseline survival rates, possibly by blocking tumor-related or normal levels of catecholamines and prostaglandins. Searching for mediating mechanisms, we found that each of the stress factors transiently suppressed NK activity against CRNK-16 and YAC-1 lines on a per NK basis. In contrast, the direct effects of stress factors on CRNK-16 proliferation, vitality, and VEGF secretion could not explain or even contradicted the in vivo survival findings. Overall, it seems that environmental stress, epinephrine, and prostaglandins promote leukemia progression in rats, potentially through suppressing cell mediated immunity. Thus, patients with hematological malignancies, which often exhibit diminished NK activity, may benefit from extended β-blockade and COX inhibition.

Treatment aimed at perioperative enhancement of CMI and simultaneous inhibition of excessive catecholamine and prostaglandin responses, employing CpG-C, propranolol, and etodolac, could be successful in limiting postoperative immunosuppression and metastatic progression, more so than each treatment alone.

No abstract

Suppression of natural killer (NK) cell activity is common following stress, has been reported to predict malignant recurrence in cancer patients, and was shown to underlie metastatic dissemination in animal models. We have previously reported that catecholamines play a major role in NK cell suppression, particularly in the context of physiological stress and surgery. In the current study using F344 rats, we examined the prophylactic use of different regimens of type-C CpG oligodeoxynucleotides (CpG-C ODN) on NK activity and metastatic dissemination in the context of pharmacological stress (using metaproterenol for β-adrenoceptor stimulation). Our results indicated that the beneficial effects of CpG-C ODN were more profound under pharmacological stress than under baseline conditions. A bolus of CpG-C ODN (330μg/kg, i.p.) 24 hrs prior to metaproterenolchallenge was most effective at reducing lung tumor retention of an experimental syngeneic mammary adenocarcinoma (MADB106), while having no observable side effects. Depletion of NK cells revealed their key role in improving baseline levels of resistance to metastatic dissemination following CpG-C ODN administration. When NK cell cytotoxicity was assessed in the circulation and the marginating-pulmonary immune compartments we found that CpG-C ODN protected individual NK cells from metaproterenol-induced suppression in both compartments. Moreover, in the critical marginating-pulmonary compartment, CpG-C ODN also elevated baseline cytotoxicity per NK cell against MADB106 tumor cells, and increased NK cell numbers in non-stressed rats. Overall, prophylactic CpG-C ODN treatment can improve immunocompetence and potentially reduce metastatic dissemination, especially in clinical settings characterized by enhanced sympathetic stress responses.

Background A unique opportunity to eradicate cancer is presented immediately after the excision of the primary tumor, but surgical procedures often induce the release of immunosuppressing factors that render cell mediated immunity ineffective. Here we tested the hypothesis that integration of peri-operative immunostimulation and blockade of immunosuppression could synergistically improve postoperative anti-metastatic immunity and long-term survival. Methods Two syngeneic tumor models in F344 rats were employed, studying postoperative tumor progression. In the first model, survival following laparotomy and CRNK-16 leukemia was studied. Rats were perioperatively treated with the immuno-stimulant poly I-C (5×0.2mg/kg/inj), with catecholamine- and prostaglandin-blockers (shown to prevent postoperative immunosuppression: 4.5mg/kg nadolol, 4mg/kg indomethacin), with both interventions, or with neither. Long-term survival was assessed thereafter. The second model used the MADB106 mammary adenocarcinoma, assessing its lung tumor retention (LTR) following i.v. inoculation, as well as host marginating-pulmonary NK numbers and activity against this tumor. IL-12 was employed for immunostimulation (4×1.5μg/kg/inj), with and without the above blockers. Results Postoperative CRNK-16 survival rates were significantly improved only by the integrated approach of immune stimulation and endocrine blockers. Postoperative MADB106 LTR was additively reduced by the two interventions. Importantly, while IL-12 increased pulmonary NK cytotoxicity against MADB106, surgery markedly suppressed this cytotoxicity in both IL-12 and vehicle treated animals. The blockers prevented this suppression per lung and per single NK cell. Conclusions Immunostimulation could be rendered ineffective postoperatively due to immunosuppression; therefore integrating endocrine-blocker therapies into the realm of perioperative immunotherapy could optimize immune control over residual disease, potentially improving clinical outcomes.

Immune stimulation by biological response modifiers is a common approach in tumor immunotherapy. IL-12 was found effective in various animal studies, but clinical trials showed limited success. However, among other differences, animal models do not simulate psychological or physiological stress while employing IL-12, whereas cancer patients often experience distress while treated with immunostimulants. Thus, in the current study we assessed the impact of continuous stress on the efficacy of IL-12 immunostimulation. F344 rats were subjected to a pharmacological stress paradigm (continuous administration of a β-adrenergic agonist) or to a 20-hr behavioral stress paradigm (wet cage exposure) commencing 2 hrs before IL-12 administration. Twenty-six hr after stress initiation, we studied indices known to reflect IL-12 immunostimulatory impacts, including NK cell numbers and activity in different immune compartments, and in vivo resistance to MADB106 lung tumor colonization. The results indicated that both the pharmacological and behavioral stress paradigms significantly reduced the increase in the number and activity of marginating-pulmonary NK cells evident in non-stressed IL-12 treated animals. Additionally, stressed animals exhibited a lower IL-12-induced improvement of MADB106 lung clearance, an in vivo index that markedly depends on total marginating-pulmonary NK activity. These deleterious effects of stress were more prominent in males than in females. Overall, the findings demonstrate that prolonged stress exposure can disrupt the efficacy of simultaneous immunostimulatory treatments, irrespective of stress effects on baseline immune measures. Neuroendocrine and cellular mediating mechanisms are yet unknown, but the potential clinical ramifications of these findings warrant consideration in clinical trials employing immunostimulatory agents.