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The Intestinotrophic Peptide, GLP-2, Counteracts the Gastrointestinal Atrophy in Mice Induced by the Epidermal Growth Factor Receptor Inhibitor, Erlotinib, and Cisplatin

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Abstract

Purpose

Erlotinib, an epidermal-growth-factor receptor inhibitor, belongs to a new generation of targeted cancer therapeutics. Gastrointestinal side-effects are common and have been markedly aggravated when erlotinib is combined with cytostatics. We examined the effects of erlotinib alone and combined with the cytostatic, cisplatin, on the gastrointestinal tract and examined whether glucagon-like peptide-2 (GLP-2), an intestinal hormone with potent intestinotrophic properties, might counteract the possible damaging effects of the treatments.

Experimental Design

Groups of ten mice were treated for 10 days with increasing doses of erlotinib alone or in combination with cisplatin and/or GLP-2. Weight and length of the gastrointestinal organs were determined and histological sections were analyzed with morphometric methods as well as BrdU- and ApopTag-staining to determine mitotic and apoptotic activity.

Results

Erlotinib was found to induce small-intestinal and colonic growth inhibition through an increased apoptotic activity but had no effect on mitotic activity. The combined treatment with cisplatin synergistically aggravated the intestinal growth inhibition. Erlotinib, and especially the combination therapy, increased the weight of the stomach contents considerably. Concomitant treatment with GLP-2 counteracted the intestinal mucosal atrophy induced both by erlotinib alone and combined with cisplatin through a reduction of the apoptotic activity. There was no influence on the mitotic activity.

Conclusions

The findings demonstrate that the intestinal mucosal damage induced by erlotinib alone and in combination with cisplatin can be counteracted by GLP-2 treatment, which might suggest a role for GLP-2 in the treatment of the gastrointestinal side-effects caused by these cancer therapeutics.

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References

  1. Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther. 1999;82(2–3):241–250.

    Article  CAS  PubMed  Google Scholar 

  2. Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006;366(1):2–16.

    Article  CAS  PubMed  Google Scholar 

  3. Siegel-Lakhai WS, Beijnen JH, Schellens JH. Current knowledge and future directions of the selective epidermal growth factor receptor inhibitors erlotinib (Tarceva) and gefitinib (Iressa). Oncologist. 2005;10(8):579–589.

    Article  CAS  PubMed  Google Scholar 

  4. Brabender J, Danenberg KD, Metzger R, et al. Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer Is correlated with survival. Clin Cancer Res. 2001;7(7):1850–1855.

    CAS  PubMed  Google Scholar 

  5. Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R. FDA drug approval summary: erlotinib (Tarceva) tablets. Oncologist. 2005;10(7):461–466.

    Article  CAS  PubMed  Google Scholar 

  6. European Agency for the Evaluation of Medicinal Products (EMEA). Tarceva® [European product information]. Available at http://www.emea.europa.eu/humandocs/PDFs/EPAR/tarceva/H-618-PI-en.pdf. Accessed March 4, 2008.

Ref Type: Generic

  1. Bareschino MA, Schettino C, Troiani T, Martinelli E, Morgillo F, Ciardiello F. Erlotinib in cancer treatment. Ann Oncol. 2007;18 (Suppl 6):vi35–vi41.

    Article  PubMed  Google Scholar 

  2. Barnard JA, Beauchamp RD, Russell WE, Dubois RN, Coffey RJ. Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology. Gastroenterology. 1995;108(2):564–580.

    Article  CAS  PubMed  Google Scholar 

  3. Dignass AU, Sturm A. Peptide growth factors in the intestine. Eur J Gastroenterol Hepatol. 2001;13(7):763–770.

    Article  CAS  PubMed  Google Scholar 

  4. Playford RJ. Peptides and gastrointestinal mucosal integrity. Gut. 1995;37(5):595–597.

    Article  CAS  PubMed  Google Scholar 

  5. Berlanga-Acosta J, Playford RJ, Mandir N, Goodlad RA. Gastrointestinal cell proliferation and crypt fission are separate but complementary means of increasing tissue mass following infusion of epidermal growth factor in rats. Gut. 2001;48(6):803–807.

    Article  CAS  PubMed  Google Scholar 

  6. Kitchen PA, Goodlad RA, FitzGerald AJ, et al. Intestinal growth in parenterally-fed rats induced by the combined effects of glucagon-like peptide 2 and epidermal growth factor. JPEN J Parenter Enteral Nutr. 2005;29(4):248–254.

    Article  CAS  PubMed  Google Scholar 

  7. Kurokowa M, Lynch K, Podolsky DK. Effects of growth factors on an intestinal epithelial cell line: transforming growth factor beta inhibits proliferation and stimulates differentiation. Biochem Biophys Res Commun. 1987;142(3):775–782.

    Article  CAS  PubMed  Google Scholar 

  8. Matsuda K, Sakamoto C, Konda Y, et al. Effects of growth factors and gut hormones on proliferation of primary cultured gastric mucous cells of guinea pig. J Gastroenterol. 1996;31(4):498–504.

    Article  CAS  PubMed  Google Scholar 

  9. Opleta-Madsen K, Hardin J, Gall DG. Epidermal growth factor upregulates intestinal electrolyte and nutrient transport. Am J Physiol. 1991;260(Pt 1 6):G807–G814.

    CAS  PubMed  Google Scholar 

  10. Goodlad RA, Raja KB, Peters TJ, Wright NA. Effects of urogastrone-epidermal growth factor on intestinal brush border enzymes and mitotic activity. Gut. 1991;32(9):994–998.

    Article  CAS  PubMed  Google Scholar 

  11. Skov OP. Role of epidermal growth factor in gastroduodenal mucosal protection. J Clin Gastroenterol. 1988;10(Suppl 1):S146–S151.

    Google Scholar 

  12. Itoh M, Imai S, Joh T, et al. Protection of gastric mucosa against ethanol-induced injury by intragastric bolus administration of epidermal growth factor combined with hydroxypropylcellulose. J Clin Gastroenterol. 1992;14(Suppl 1):S127–S130.

    Article  PubMed  Google Scholar 

  13. Dignass AU, Podolsky DK. Cytokine modulation of intestinal epithelial cell restitution: central role of transforming growth factor beta. Gastroenterology. 1993;105(5):1323–1332.

    CAS  PubMed  Google Scholar 

  14. Itoh M, Matsuo Y. Gastric ulcer treatment with intravenous human epidermal growth factor: a double-blind controlled clinical study. J Gastroenterol Hepatol. 1994;9(Suppl 1):S78–S83.

    Article  PubMed  Google Scholar 

  15. Messersmith WA, Laheru DA, Senzer NN, et al. Phase I trial of irinotecan, infusional 5-fluorouracil, and leucovorin (FOLFIRI) with erlotinib (OSI-774): early termination due to increased toxicities. Clin Cancer Res. 2004;10(19):6522–6527.

    Article  CAS  PubMed  Google Scholar 

  16. Drucker DJ, Erlich P, Asa SL, Brubaker PL. Induction of intestinal epithelial proliferation by glucagon-like peptide 2. Proc Natl Acad Sci U S A. 1996;93(15):7911–7916.

    Article  CAS  PubMed  Google Scholar 

  17. Drucker DJ, Shi Q, Crivici A, et al. Regulation of the biological activity of glucagon-like peptide 2 in vivo by dipeptidyl peptidase IV. Nat Biotechnol. 1997;15(7):673–677.

    Article  CAS  PubMed  Google Scholar 

  18. Hartmann B, Thulesen J, Kissow H, et al. Dipeptidyl peptidase IV inhibition enhances the intestinotrophic effect of glucagon-like peptide-2 in rats and mice. Endocrinology. 2000;141(11):4013–4020.

    Article  CAS  PubMed  Google Scholar 

  19. Tsai CH, Hill M, Asa SL, Brubaker PL, Drucker DJ. Intestinal growth-promoting properties of glucagon-like peptide-2 in mice. Am J Physiol. 1997;273(1 Pt 1):E77–E84.

    CAS  PubMed  Google Scholar 

  20. Dube PE, Brubaker PL. Frontiers in glucagon-like peptide-2: multiple actions, multiple mediators. Am J Physiol Endocrinol Metab. 2007;293(2):E460–E465.

    Article  CAS  PubMed  Google Scholar 

  21. Dube PE, Forse CL, Bahrami J, Brubaker PL. The essential role of insulin-like growth factor-1 in the intestinal tropic effects of glucagon-like peptide-2 in mice. Gastroenterology. 2006;131(2):589–605.

    Article  CAS  PubMed  Google Scholar 

  22. Drucker DJ, Yusta B, Boushey RP, DeForest L, Brubaker PL. Human [Gly2]GLP-2 reduces the severity of colonic injury in a murine model of experimental colitis. Am J Physiol. 1999;276(1 Pt 1):G79–G91.

    CAS  PubMed  Google Scholar 

  23. L’Heureux MC, Brubaker PL. Glucagon-like peptide-2 and common therapeutics in a murine model of ulcerative colitis. J Pharmacol Exp Ther. 2003;306(1):347–354.

    Article  PubMed  Google Scholar 

  24. Orskov C, Hartmann B, Poulsen SS, Thulesen J, Hare KJ, Holst JJ. GLP-2 stimulates colonic growth via KGF, released by subepithelial myofibroblasts with GLP-2 receptors. Regul Pept. 2005;124(1–3):105–112.

    Article  CAS  PubMed  Google Scholar 

  25. Dube PE, Forse CL, Bahrami J, Brubaker PL. The essential role of insulin-like growth factor-1 in the intestinal tropic effects of glucagon-like peptide-2 in mice. Gastroenterology. 2006;131(2):589–605.

    Article  CAS  PubMed  Google Scholar 

  26. Yusta B, Holland D, Koehler JA, et al. ErbB signaling is required for the proliferative actions of GLP-2 in the murine gut. Gastroenterology. 2009;137(3):986–996.

    Article  CAS  PubMed  Google Scholar 

  27. Jeppesen PB, Sanguinetti EL, Buchman A, et al. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut. 2005;54(9):1224–1231.

    Article  CAS  PubMed  Google Scholar 

  28. Wallis K, Walters JR, Forbes A. Review article: glucagon-like peptide 2–current applications and future directions. Aliment Pharmacol Ther. 2007;25(4):365–372.

    Article  CAS  PubMed  Google Scholar 

  29. Kjellev S, Lundsgaard D, Poulsen SS, Markholst H. Reconstitution of Scid mice with CD4+. Int Immunopharmacol. 2006;6(8):1341–1354.

    Article  CAS  PubMed  Google Scholar 

  30. Hare KJ, Hartmann B, Kissow H, Holst JJ, Poulsen SS. The intestinotrophic peptide, GLP-2, counteracts intestinal atrophy in mice induced by the epidermal growth factor receptor inhibitor, gefitinib. Clin Cancer Res. 2007;13(17):5170–5175.

    Article  CAS  PubMed  Google Scholar 

  31. Stringer AM, Gibson RJ, Bowen JM, Logan RM, Yeoh AS, Keefe DM. Chemotherapy-induced mucositis: the role of gastrointestinal microflora and mucins in the luminal environment. J Support Oncol. 2007;5(6):259–267.

    CAS  PubMed  Google Scholar 

  32. Jeppesen PB, Hartmann B, Thulesen J, et al. Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon. Gastroenterology. 2001;120(4):806–815.

    Article  CAS  PubMed  Google Scholar 

  33. Wojdemann M, Wettergren A, Hartmann B, Holst JJ. Glucagon-like peptide-2 inhibits centrally induced antral motility in pigs. Scand J Gastroenterol. 1998;33(8):828–832.

    Article  CAS  PubMed  Google Scholar 

  34. Wojdemann M, Wettergren A, Hartmann B, Hilsted L, Holst JJ. Inhibition of sham feeding-stimulated human gastric acid secretion by glucagon-like peptide-2. J Clin Endocrinol Metab. 1999;84(7):2513–2517.

    Article  CAS  PubMed  Google Scholar 

  35. Nagell CF (2004) Glucagon-like peptide-2 inhibits antral emptying in man, but is not as potent as glucagon-like peptide-1.

  36. Boushey RP, Yusta B, Drucker DJ. Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis. Am J Physiol. 1999;277(5 Pt 1):E937–E947.

    CAS  PubMed  Google Scholar 

  37. Boushey RP, Yusta B, Drucker DJ. Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated mortality and enhances cell survival in cells expressing a transfected GLP-2 receptor. Cancer Res. 2001;61(2):687–693.

    CAS  PubMed  Google Scholar 

  38. Tavakkolizadeh A, Shen R, Abraham P, et al. Glucagon-like peptide 2: a new treatment for chemotherapy-induced enteritis. J Surg Res. 2000;91(1):77–82.

    Article  CAS  PubMed  Google Scholar 

  39. Thulesen J, Hartmann B, Hare KJ, et al. Glucagon-like peptide 2 (GLP-2) accelerates the growth of colonic neoplasms in mice. Gut. 2004;53(8):1145–1150.

    Article  CAS  PubMed  Google Scholar 

  40. Koehler JA, Harper W, Barnard M, Yusta B, Drucker DJ. Glucagon-like peptide-2 does not modify the growth or survival of murine or human intestinal tumor cells. Cancer Res. 2008;68(19):7897–7904.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Andreas Rosén Rasmussen is the recipient of a scholarship from the Danish Agency for Science, Technology and Innovation. The technical assistance of Heidi Paulsen and Jette Schousboe is highly appreciated.

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Authors and Affiliations

  1. Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, 3 Blegdamsvej, 2200, Copenhagen N, Denmark

    Andreas Rosén Rasmussen, Niels-Erik Viby, Kristine Juul Hare, Bolette Hartmann, Jens Juul Holst & Steen Seier Poulsen

  2. Novo Nordisk A/S, Novo Nordisk Park, 2760, Måløv, Denmark

    Lars Thim

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  1. Andreas Rosén Rasmussen
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Correspondence to Steen Seier Poulsen.

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Rasmussen, A.R., Viby, NE., Hare, K.J. et al. The Intestinotrophic Peptide, GLP-2, Counteracts the Gastrointestinal Atrophy in Mice Induced by the Epidermal Growth Factor Receptor Inhibitor, Erlotinib, and Cisplatin. Dig Dis Sci 55, 2785–2796 (2010). https://doi.org/10.1007/s10620-009-1104-x

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