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Improving Postoperative Immune Status and Resistance to Cancer Metastasis: A Combined Perioperative Approach of Immunostimulation and Prevention of Excessive Surgical Stress Responses

Goldfarb, Yael MSc; Sorski, Liat MA; Benish, Marganit MA; Levi, Ben MA; Melamed, Rivka PhD; Ben-Eliyahu, Shamgar PhD

doi: 10.1097/SLA.0b013e318211d7b5
Original Articles

Background: Surgical procedures, including primary tumor resection, have been suggested to suppress immune competence and to promote postoperative infections and cancer metastasis. Catecholamines and prostaglandins were recently implicated in these processes, and in directly promoting tumor angiogenesis and invasion.

Objective: To examine the integration of 2 complementary approaches to reduce postoperative immunosuppression and metastatic progression: (1) perioperative immunostimulation with CpG-C and (2) pharmacological blockade of the tumor-promoting and immunosuppressing effects of catecholamines and prostaglandins, using propranolol (P) and etodolac (E), respectively.

Methods: F344 rats were treated before surgery with CpG-C, P+E, both interventions, or vehicles, and were intravenously inoculated with syngeneic MADB106 mammary adenocarcinoma cells. Blood was withdrawn, marginating-pulmonary leukocytes were harvested, and NK activity and lung MADB106 tumor retention were assessed. In addition, C57BL/6 mice were implanted with syngeneic B16F10.9 melanoma cells. When tumors reached 100 mm3, mice were treated with CpG-C/vehicle, and 24 hours later the tumor was excised along with P+E/vehicle treatment. Recurrence-free survival was monitored thereafter.

Results: Each of the regimens alone, CpG-C or P+E, showed improvement in most indices examined, including improved long-term recurrence-free survival rates. Most importantly, the combined treatment yielded additive or synergistic effects, further improving tumor clearance from the lungs and enhancing NK numbers and cytotoxicity via different, but complimentary, mechanisms.

Conclusions: 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.

This study in rats and mice demonstrates synergistic perioperative beneficial effects of immunostimulation (CpG-C), β-adrenoceptor blockade (propranolol), and COX2 inhibition (etodolac). The treatment improved postoperative NK numbers and cytotoxicity in the circulation and lungs, tumor cell clearance from the lungs, and recurrence-free survival rates following excision of a metastasizing tumor.

From the Neuroimmunology Research Unit, Department of Psychology, Tel-Aviv University, Tel-Aviv 69978, Israel.

Reprints: Shamgar Ben-Eliyahu, Department of Psychology, Tel-Aviv University, Tel-Aviv 69978, Israel. E-mail: shamgar@post.tau.ac.il.

Supported by NIH/NCI Grant No. CA125456 (SBE), a grant from the Israel-USA Bi-national Science Foundation No. 2005331 (SBE), and funding from the Center for Absorption in Science of the Israeli Ministry of Immigrant Absorption (YG).

© 2011 Lippincott Williams & Wilkins, Inc.