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Perioperative Use of β-blockers and COX-2 Inhibitors May Improve Immune Competence and Reduce the Risk of Tumor Metastasis

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

COX inhibitors and β-blockers were recently suggested to reduce cancer progression through inhibition of tumor proliferation and growth factor secretion, induction of tumor apoptosis, and prevention of cellular immune suppression during the critical perioperative period. Here we evaluated the perioperative impact of clinically applicable drugs from these categories in the context of surgery, studying natural killer (NK) cell activity and resistance to experimental metastases.

Methods

F344 rats were treated with COX-1 inhibitors (SC560), COX-2 inhibitors (indomethacin, etodolac, or celecoxib), a β-blocker (propranolol), or a combination of a COX-2 inhibitor and a β-blocker (etodolac and propranolol). Rats underwent laparotomy, and were inoculated intravenously with syngeneic MADB106 tumor cells for the assessment of lung tumor retention (LTR). Additionally, the impact of these drug regimens on postoperative levels of NK cytotoxicity was studied in peripheral blood and marginating-pulmonary leukocytes.

Results

Surgery increased MADB106 LTR. COX-2 inhibition, but not COX-1 inhibition, reduced postoperative LTR. Etodolac and propranolol both attenuated the deleterious impact of surgery, and their combined use abolished it. Surgery decreased NK cytotoxicity per NK cell in both immune compartments, and only the combination of etodolac and propranolol significantly attenuated these effects. Lastly, the initiation of drug treatment three days prior to surgery yielded the same beneficial effects as a single pre-operative administration, but, as discussed, prolonged treatment may be more advantageous clinically.

Conclusions

Excess prostaglandin and catecholamine release contributes to postoperative immune-suppression. Treatment combining perioperative COX-2 inhibition and β-blockade is practical in operated cancer patients, and our study suggests potential immunological and clinical benefits.

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Acknowledgement

Support was provided by NIH/NCI CA125456 grant (S. B-E) and by a grant from the Israel-USA Binational Science Foundation (S. B-E).

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Authors and Affiliations

  1. NeuroImmunology Research Unit, Department of Psychology, Tel Aviv University, Tel Aviv, 69978, Israel

    Marganit Benish MA, Inbal Bartal MA, Yael Goldfarb MSc, Ben Levi MA, Roi Avraham MA & Shamgar Ben-Eliyahu PhD

  2. Department of Biochemistry, Tel Aviv University, Tel Aviv, Israel

    Amiram Raz PhD

  3. Outcomes Research(TM) Institute, Louisville, KY, USA

    Shamgar Ben-Eliyahu PhD

Authors
  1. Marganit Benish MA
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  2. Inbal Bartal MA
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Correspondence to Shamgar Ben-Eliyahu PhD.

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Benish, M., Bartal, I., Goldfarb, Y. et al. Perioperative Use of β-blockers and COX-2 Inhibitors May Improve Immune Competence and Reduce the Risk of Tumor Metastasis. Ann Surg Oncol 15, 2042–2052 (2008). https://doi.org/10.1245/s10434-008-9890-5

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  • DOI: https://doi.org/10.1245/s10434-008-9890-5

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