Skip to main content

Advertisement

SpringerLink
Log in

Effect of beta blocker combined with COX-2 inhibitor on colonic anastomosis in rats

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

Pharmacologic modulation of the perioperative physiologic stress response, using the beta-blocker propranolol, combined with the COX-2 inhibitor etodolac, has been shown to reduce metastatic spread and increase survival rates following surgery for primary tumor excision in rodents. Prior to implantation of this pharmacological approach in clinical trials in patients with colon cancer, the safety of this technique has to be evaluated. This study assessed the effects of these drugs on the healing of colonic anastomosis in rats.

Methods

Forty-eight F344 rats were divided into two groups, which were given seven daily subcutaneous injections of either vehicle, or propranolol (up to 1.2 mg/kg/day) combined with etodolac (12.5 mg/kg/day), starting the day before surgery. Each animal underwent laparotomy, colotomy of the descending colon, and anastomosis. Anastomotic leak rate and bursting pressure were compared at 1 week after the operation. The harvested anastomosis was histologically assessed for wound healing parameters.

Results

Forty-three rats survived the operation and were eligible for analysis at 1 week. No significant difference in survival, anastomotic leakage, or bursting pressure was found between animals that received propranolol and etodolac versus those receiving vehicle (drugs 179 mmHg ± 45.4; vehicle 187 mmHg, SD ± 35.0, p = 0.54). Histologic assessment of fibrosis, necrosis, cell infiltration, and tissue reaction zone did not differ between the two groups.

Conclusions

Perioperative administration of propranolol and etodolac seems safe in colon operations in rats and does not affect anastomotic failure or colon healing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Shakhar G, Ben-Eliyahu S (2003) Potential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological patients? Ann Surg Oncol 10:972–992

    Article  PubMed  Google Scholar 

  2. Lutgendorf SK, Cole S, Costanzo E, Bradley S, Coffin J, Jabbari S, Rainwater K, Ritchie JM, Yang M, Sood AK (2003) Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. Clin Cancer Res 9:4514–4521

    CAS  PubMed  Google Scholar 

  3. Wojtowicz-Praga S (1997) Reversal of tumor-induced immunosuppression: a new approach to cancer therapy. J Immunother 20:165–177

    Article  CAS  PubMed  Google Scholar 

  4. Oosterling SJ, van der Bij GJ, van Egmond M, van der Sijp JR (2005) Surgical trauma and peritoneal recurrence of colorectal carcinoma. Eur J Surg Oncol 31:29–37

    Article  CAS  PubMed  Google Scholar 

  5. van der Bij GJ, Oosterling SJ, Beelen RH, Meijer S, Coffey JC, van Egmond M (2009) The perioperative period is an underutilized window of therapeutic opportunity in patients with colorectal cancer. Ann Surg 249:727–734

    Article  PubMed  Google Scholar 

  6. Zetter BR (1998) Angiogenesis and tumor metastasis. Annu Rev Med 49:407–424

    Article  CAS  PubMed  Google Scholar 

  7. Kern MA, Haugg AM, Koch AF, Schilling T, Breuhahn K, Walczak H et al (2006) Cyclooxygenase-2 inhibition induces apoptosis signaling via death receptors and mitochondria in hepatocellular carcinoma. Cancer Res 66:7059–7066

    Article  CAS  PubMed  Google Scholar 

  8. Wei D, Wang L, He Y et al (2004) Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res 64:2030–2038

    Article  CAS  PubMed  Google Scholar 

  9. Svane IM, Boesen M, Engel AM (1999) The role of cytotoxic T-lymphocytes in the prevention and immune surveillance of tumors—lessons from normal and immunodeficient mice. Med Oncol 16:223–38

    Article  CAS  PubMed  Google Scholar 

  10. van Egmond M (2008) Neutrophils in antibody-based immunotherapy of cancer. Expert Opin Biol Ther 8:83–94

    Article  PubMed  Google Scholar 

  11. van der Bij GJ, Oosterling SJ, Meijer S, Beelen RH, van Egmond M (2005) The role of macrophages in tumor development. Cell Oncol 27:203–213

    PubMed  Google Scholar 

  12. Rozic JG, Chakraborty C, Lala PK (2001) Cyclooxygenase inhibitors retard murine mammary tumor progression by reducing tumor cell migration, invasiveness and angiogenesis. Int J Cancer 93:497–506

    Article  CAS  PubMed  Google Scholar 

  13. Thaker PH, Han LY, Kamat AA et al (2006) Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med 12:939–944

    Article  CAS  PubMed  Google Scholar 

  14. Masur K, Niggemann B, Zanker KS et al (2001) Norepinephrine induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res 61:2866–2869

    CAS  PubMed  Google Scholar 

  15. Sood AK, Bhatty R, Kamat AA et al (2006) Stress hormone-mediated invasion of ovarian cancer cells. Clin Cancer Res 12:369–375

    Article  CAS  PubMed  Google Scholar 

  16. Melamed R, Rosenne E, Shakhar K et al (2005) Marginating pulmonary-NK activity and resistance to experimental tumor metastasis: suppression by surgery and the prophylactic use of a beta-adrenergic antagonist and a prostaglandin synthesis inhibitor. Brain Behav Immun 19:114–126

    Article  CAS  PubMed  Google Scholar 

  17. Benish M, Bartal I, Goldfarb Y et al (2008) Perioperative use of beta-blockers and cyclooxygenase-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Ann Surg Oncol 15:2042–2052

    Article  PubMed  Google Scholar 

  18. Glasner A, Avraham R, Rosenne E, Benish M, Zmora O, Shemer S, Meiboom H, Ben-Eliyahu S (2010) Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol 184:2449–2457

    Article  CAS  PubMed  Google Scholar 

  19. Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659

    Article  CAS  PubMed  Google Scholar 

  20. Shi JM, Lai SG, Xu CJ et al (2004) Pharmacokinetic difference between S-(+)- and R-(−)-etodolac in rats. Acta Pharmacol Sin 25:996–999

    CAS  PubMed  Google Scholar 

  21. Barnes PJ, Adcock I (1993) Anti-inflammatory actions of steroids: molecular mechanisms. Trends Pharmacol Sci 14:436–441

    Article  CAS  PubMed  Google Scholar 

  22. Eschwege P, Dumas F, Blanchet P, Le Maire V, Benoit G, Jardin A, Lacour B, Loric S (1995) Haematogenous dissemination of prostatic epithelial cells during radical prostatectomy. Lancet 346(8989):1528–1530

    Article  CAS  PubMed  Google Scholar 

  23. Yamaguchi K, Takagi Y, Aoki S, Saji S (2000) Significant detection of circulating cancer cells in the blood by reverse transcriptase-polymerase chain reaction during colorectal cancer resection. Ann Surg 232:58–65

    Article  CAS  PubMed  Google Scholar 

  24. Ben-Eliyahu S (1998) Stress, natural killer cell activity, and tumor metastasis: the role of catecholamines and corticosteroids. In: Levi A et al (eds) New frontiers in stress research: modulation in brain function. Harwood Academic Publishers GmbH, Amsterdam, pp 203–215

    Google Scholar 

  25. Page GG, Ben-Eliyahu S, Liebeskind JC (1994) The role of LGL/NK cells in surgery-induced promotion of metastasis and its attenuation by morphine. Brain Behav Immun 8:241–250

    Article  CAS  PubMed  Google Scholar 

  26. Thompson SD, Chang EU, Jobe BA (2006) Clinical review: healing in gastrointestinal anastomoses. Microsurgery 26:131–136

    Article  PubMed  Google Scholar 

  27. Cahill RA, Sheehan KM, Scanlon RW et al (2004) Effects of COX-2 inhibitor on colonic anastomotic and skin wound integrity. Br J Surg 12:1613–1618

    Article  Google Scholar 

  28. de Hingh IH, van Goor H, de Man BM et al (2006) Selective COX-2 inhibitors impair ileal but not colonic experimental anastomotic healing in the early postoperative period. Br J Surg 4:489–497

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, Meir Medical Center, Tel Aviv, Israel

    Barak Benjamin

  2. Neuroimmunology Research Unit, Department of Psychology, Tel Aviv University, Tel Aviv, Israel

    Ofir Hazut, Lee Shaashua, Marganit Benish & Shamgar Ben-Eliyahu

  3. Department of Pathology, Sheba Medical Center, Tel Aviv, Israel

    Iris Barshack

  4. Department of Surgery and Transplantation, Sheba Medical Center, Tel-Hashomer, 52621, Israel

    Niv Zmora, Aviad Hoffman & Oded Zmora

Authors
  1. Barak Benjamin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ofir Hazut
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lee Shaashua
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marganit Benish
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Niv Zmora
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Iris Barshack
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aviad Hoffman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shamgar Ben-Eliyahu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Oded Zmora
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Oded Zmora.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Benjamin, B., Hazut, O., Shaashua, L. et al. Effect of beta blocker combined with COX-2 inhibitor on colonic anastomosis in rats. Int J Colorectal Dis 25, 1459–1464 (2010). https://doi.org/10.1007/s00384-010-0992-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-010-0992-8

Keywords

Search

Navigation