Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis.
BACKGROUND
COX inhibitors and beta-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 beta-blocker (propranolol), or a combination of a COX-2 inhibitor and a beta-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 beta-blockade is practical in operated cancer patients, and our study suggests potential immunological and clinical benefits.
Benish
Marganit
M
NeuroImmunology Research Unit, Department of Psychology, Tel Aviv University, Tel Aviv, 69978, Israel.
Bartal
Inbal
I
Goldfarb
Yael
Y
Levi
Ben
B
Avraham
Roi
R
Raz
Amiram
A
Ben-Eliyahu
Shamgar
S
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D007109:Immunity / Q000187:drug effects*; D007694:Killer Cells, Natural / Q000187:drug effects*; D008297:Male; D009362:Neoplasm Metastasis / Q000276:immunology* / Q000517:prevention & control*; D019990:Perioperative Care; D051381:Rats; D011916:Rats, Inbred F344; D012307:Risk Factors
D000319:Adrenergic beta-Antagonists; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors