title: Improving postoperative immune status and resistance to cancer metastasis: a combined perioperative approach of immunostimulation and prevention of excessive surgical stress responses.
abstract: 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 Blood was withdrawn, marginating-pulmonary leukocytes were harvested, and NK activity and lung MADB106 tumor retention were assessed.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 mm, 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.
authors.affiliation: Neuroimmunology Research Unit, Department of Psychology, Tel-Aviv University, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Goldfarb
authors.forename: Liat
authors.initials: L
authors.lastname: Sorski
authors.forename: Marganit
authors.initials: M
authors.lastname: Benish
authors.forename: Ben
authors.initials: B
authors.lastname: Levi
authors.forename: Rivka
authors.initials: R
authors.lastname: Melamed
authors.forename: Shamgar
authors.initials: S
authors.lastname: Ben-Eliyahu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017024:Chemotherapy, Adjuvant; D004195:Disease Models, Animal; D017308:Etodolac / Q000494:pharmacology; D005260:Female; D007108:Immune Tolerance; D016867:Immunocompromised Host / Q000187:drug effects*; D016233:Immunotherapy, Active / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000276:immunology* / Q000517:prevention & control*; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy / Q000276:immunology* / Q000601:surgery*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D019990:Perioperative Care / Q000379:methods; D011183:Postoperative Complications / Q000517:prevention & control; D011433:Propranolol / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D013315:Stress, Psychological / Q000209:etiology / Q000517:prevention & control; D014407:Tumor Cells, Cultured
chemical_list: C527702:CpG ODN 2395; D009838:Oligodeoxyribonucleotides; D017308:Etodolac; D011433:Propranolol