Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1996 Sep;74(5):711–716. doi: 10.1038/bjc.1996.426

The effects of 5-fluorouracil and interferon-alpha on early healing of experimental intestinal anastomoses.

J W de Waard 1, T Wobbes 1, B M de Man 1, C J van der Linden 1, T Hendriks 1
PMCID: PMC2074708  PMID: 8795572

Abstract

The continuing search for effective adjuvant therapy after resection of intestinal malignancies has prompted a growing interest in both immediate post-operative regional chemotherapy and the combination of 5-fluorouracil (5-FU) and interferon-alpha as drugs of choice. We have compared the effects of both compounds, alone and together, on early healing of intestinal anastomoses. Four groups (n = 26 each) of rats underwent resection and anastomosis of both ileum and colon: a control group and three groups receiving intraperitoneal 5-FU, interferon-alpha or both on the day of surgery and the next 2 days. Animals were killed 3 or 7 days (n = 10 each) after operation in order to measure anastomotic strength and hydroxyproline content. The remaining six animals in each group were used to study anastomotic collagen synthetic capacity at day 3. Three days after operation, ileal anastomotic bursting pressure was lowered by 37% in the 5-FU/interferon-alpha group (P = 0.0104). At day 7, anastomotic breaking strength was reduced significantly in ileum (P = 0.0221) and colon (P = 0.0054) of the 5-FU/interferon-alpha group and in colon of the interferon-alpha group (P = 0.0221). Collagen synthetic capacity was strongly suppressed by 5-FU but not by interferon-alpha. However, no differences in anastomotic hydroxyproline content were observed between groups at both days 3 and 7. Thus, post-operative use of interferon-alpha, in particular in combination with 5-FU, may be detrimental to anastomotic repair in the intestine.

Full text

PDF
711

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bhartiya D., Sklarsh J. W., Maheshwari R. K. Enhanced wound healing in animal models by interferon and an interferon inducer. J Cell Physiol. 1992 Feb;150(2):312–319. doi: 10.1002/jcp.1041500214. [DOI] [PubMed] [Google Scholar]
  2. Cunliffe W. J., Sugarbaker P. H. Gastrointestinal malignancy: rationale for adjuvant therapy using early postoperative intraperitoneal chemotherapy. Br J Surg. 1989 Oct;76(10):1082–1090. doi: 10.1002/bjs.1800761030. [DOI] [PubMed] [Google Scholar]
  3. Duncan M. R., Berman B. Gamma interferon is the lymphokine and beta interferon the monokine responsible for inhibition of fibroblast collagen production and late but not early fibroblast proliferation. J Exp Med. 1985 Aug 1;162(2):516–527. doi: 10.1084/jem.162.2.516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Duncan M. R., Hasan A., Berman B. Pentoxifylline, pentifylline, and interferons decrease type I and III procollagen mRNA levels in dermal fibroblasts: evidence for mediation by nuclear factor 1 down-regulation. J Invest Dermatol. 1995 Feb;104(2):282–286. doi: 10.1111/1523-1747.ep12612819. [DOI] [PubMed] [Google Scholar]
  5. Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med. 1995 Dec 28;333(26):1757–1763. doi: 10.1056/NEJM199512283332608. [DOI] [PubMed] [Google Scholar]
  6. Graf W., Weiber S., Glimelius B., Jiborn H., Påhlman L., Zederfeldt B. Influence of 5-fluorouracil and folinic acid on colonic healing: an experimental study in the rat. Br J Surg. 1992 Aug;79(8):825–828. doi: 10.1002/bjs.1800790840. [DOI] [PubMed] [Google Scholar]
  7. Granstein R. D., Deak M. R., Jacques S. L., Margolis R. J., Flotte T. J., Whitaker D., Long F. H., Amento E. P. The systemic administration of gamma interferon inhibits collagen synthesis and acute inflammation in a murine skin wounding model. J Invest Dermatol. 1989 Jul;93(1):18–27. doi: 10.1111/1523-1747.ep12277336. [DOI] [PubMed] [Google Scholar]
  8. Granstein R. D., Flotte T. J., Amento E. P. Interferons and collagen production. J Invest Dermatol. 1990 Dec;95(6 Suppl):75S–80S. doi: 10.1111/1523-1747.ep12874789. [DOI] [PubMed] [Google Scholar]
  9. Grem J. L., McAtee N., Murphy R. F., Balis F. M., Steinberg S. M., Hamilton J. M., Sorensen J. M., Sartor O., Kramer B. S., Goldstein L. J. A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma. J Clin Oncol. 1991 Oct;9(10):1811–1820. doi: 10.1200/JCO.1991.9.10.1811. [DOI] [PubMed] [Google Scholar]
  10. Grem J. L., van Groeningen C. J., Ismail A. A., Johnston P. G., Alexander H. R., Allegra C. J. The role of interferon-alpha as a modulator of fluorouracil and leucovorin. Eur J Cancer. 1995 Jul-Aug;31A(7-8):1316–1320. doi: 10.1016/0959-8049(95)91267-g. [DOI] [PubMed] [Google Scholar]
  11. Harris D. T., Mastrangelo M. J. Theory and application of early systemic therapy. Semin Oncol. 1991 Dec;18(6):493–503. [PubMed] [Google Scholar]
  12. Hesp F. L., Hendriks T., Lubbers E. J., deBoer H. H. Wound healing in the intestinal wall. A comparison between experimental ileal and colonic anastomoses. Dis Colon Rectum. 1984 Feb;27(2):99–104. doi: 10.1007/BF02553985. [DOI] [PubMed] [Google Scholar]
  13. Hujanen E. S., Väisänen A., Zheng A., Tryggvason K., Turpeenniemi-Hujanen T. Modulation of M(r) 72,000 and M(r) 92,000 type-IV collagenase (gelatinase A and B) gene expression by interferons alpha and gamma in human melanoma. Int J Cancer. 1994 Aug 15;58(4):582–586. doi: 10.1002/ijc.2910580422. [DOI] [PubMed] [Google Scholar]
  14. Jimenez S. A., Freundlich B., Rosenbloom J. Selective inhibition of human diploid fibroblast collagen synthesis by interferons. J Clin Invest. 1984 Sep;74(3):1112–1116. doi: 10.1172/JCI111480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kemeny N., Lokich J. J., Anderson N., Ahlgren J. D. Recent advances in the treatment of advanced colorectal cancer. Cancer. 1993 Jan 1;71(1):9–18. doi: 10.1002/1097-0142(19930101)71:1<9::aid-cncr2820710104>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  16. Mallat A., Preaux A. M., Blazejewski S., Rosenbaum J., Dhumeaux D., Mavier P. Interferon alfa and gamma inhibit proliferation and collagen synthesis of human Ito cells in culture. Hepatology. 1995 Apr;21(4):1003–1010. [PubMed] [Google Scholar]
  17. Martens M. F., Hendriks T. Postoperative changes in collagen synthesis in intestinal anastomoses of the rat: differences between small and large bowel. Gut. 1991 Dec;32(12):1482–1487. doi: 10.1136/gut.32.12.1482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Martens M. F., de Man B. M., Hendriks T., Goris R. J. Collagen synthetic capacity throughout the uninjured and anastomosed intestinal wall. Am J Surg. 1992 Oct;164(4):354–360. doi: 10.1016/s0002-9610(05)80904-3. [DOI] [PubMed] [Google Scholar]
  19. Miles R. H., Paxton T. P., Zacheis D., Dries D. J., Gamelli R. L. Systemic administration of interferon-gamma impairs wound healing. J Surg Res. 1994 Mar;56(3):288–294. doi: 10.1006/jsre.1994.1045. [DOI] [PubMed] [Google Scholar]
  20. Moertel C. G. Chemotherapy for colorectal cancer. N Engl J Med. 1994 Apr 21;330(16):1136–1142. doi: 10.1056/NEJM199404213301608. [DOI] [PubMed] [Google Scholar]
  21. Pazdur R. Fluorouracil and recombinant interferon alfa-2a in advanced gastrointestinal neoplasms. Br J Haematol. 1991 Oct;79 (Suppl 1):56–59. doi: 10.1111/j.1365-2141.1991.tb08121.x. [DOI] [PubMed] [Google Scholar]
  22. Påhlman L. Open trials in colorectal cancer. Eur J Surg Oncol. 1995 Aug;21(4):347–351. doi: 10.1016/s0748-7983(95)92186-9. [DOI] [PubMed] [Google Scholar]
  23. Sen G. C., Lengyel P. The interferon system. A bird's eye view of its biochemistry. J Biol Chem. 1992 Mar 15;267(8):5017–5020. [PubMed] [Google Scholar]
  24. Smith P. K., Krohn R. I., Hermanson G. T., Mallia A. K., Gartner F. H., Provenzano M. D., Fujimoto E. K., Goeke N. M., Olson B. J., Klenk D. C. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985 Oct;150(1):76–85. doi: 10.1016/0003-2697(85)90442-7. [DOI] [PubMed] [Google Scholar]
  25. Stout A. J., Gresser I., Thompson W. D. Inhibition of wound healing in mice by local interferon alpha/beta injection. Int J Exp Pathol. 1993 Feb;74(1):79–85. [PMC free article] [PubMed] [Google Scholar]
  26. Wadler S., Lembersky B., Atkins M., Kirkwood J., Petrelli N. Phase II trial of fluorouracil and recombinant interferon alfa-2a in patients with advanced colorectal carcinoma: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1991 Oct;9(10):1806–1810. doi: 10.1200/JCO.1991.9.10.1806. [DOI] [PubMed] [Google Scholar]
  27. Wahl L. M., Corcoran M. L. Regulation of monocyte/macrophage metalloproteinase production by cytokines. J Periodontol. 1993 May;64(5 Suppl):467–473. [PubMed] [Google Scholar]
  28. de Roy van Zuidewijn D. B., Hendriks T., Wobbes T., de Boer H. H. Intraperitoneal cytostatics impair healing of experimental intestinal anastomoses. Br J Cancer. 1991 Jun;63(6):937–941. doi: 10.1038/bjc.1991.205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. de Waard J. W., Wobbes T., Hendriks T. Early post-operative 5-fluorouracil does not affect the healing of experimental intestinal anastomoses. Int J Colorectal Dis. 1993 Sep;8(3):175–178. doi: 10.1007/BF00341194. [DOI] [PubMed] [Google Scholar]
  30. de Waard J. W., Wobbes T., de Man B. M., van der Linden C. J., Hendriks T. Post-operative levamisole may compromise early healing of experimental intestinal anastomoses. Br J Cancer. 1995 Aug;72(2):456–460. doi: 10.1038/bjc.1995.355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. de Waard J. W., Wobbes T., van der Linden C. J., Hendriks T. Retinol may promote fluorouracil-suppressed healing of experimental intestinal anastomoses. Arch Surg. 1995 Sep;130(9):959–965. doi: 10.1001/archsurg.1995.01430090045017. [DOI] [PubMed] [Google Scholar]
  32. van der Meide P. H., Dijkema R., Caspers M., Vijverberg K., Schellekens H. Cloning, expression, and purification of rat IFN-alpha 1. Methods Enzymol. 1986;119:441–453. doi: 10.1016/0076-6879(86)19064-1. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES