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Pediatric Surgery International

Published in:

01-03-2012 | Original Article

Glutamine prevents intestinal mucosal injury induced by cyclophosphamide in rats

Authors: Mitsugu Owari, Masafumi Wasa, Takaharu Oue, Satoko Nose, Masahiro Fukuzawa

Published in: Pediatric Surgery International | Issue 3/2012

Abstract

Purpose

High doses of anticancer drugs often damage the intestinal mucosa. The purpose of the present study was to examine the effect of glutamine on mucosal damage induced by cyclophosphamide in a rat model, and to elucidate the mechanisms responsible for its protective effects.

Method

Rats were randomly assigned to one of the three experimental groups. Group A (control) (n = 8): intraperitoneal injection of saline, group B (n = 8): intraperitoneal injection of cyclophosphamide (300 mg/kg), group C (n = 8): intraperitoneal injection of cyclophosphamide (300 mg/kg) and oral glutamine (1.0 g/kg). After 3 days, the ileal segment was removed for morphological and the biochemical analyses. We also evaluated the level of mucosal apoptosis by the TUNEL method and enterocyte proliferation using bromodeoxyuridine (BrdU).

Results

Mucosal atrophy was observed in group B but not in groups A or C. The mucosal wet weight, protein and glutathione levels were significantly decreased in group B compared with group A, and were increased significantly in group C compared with group B. While enterocyte proliferation significantly decreased and the apoptotic index significantly increased in group B compared with group A, a significant increase in the enterocyte proliferation and a significant decrease in apoptosis were observed in group C compared with group B.

Conclusions

Glutamine prevented intestinal mucosal injury induced by cyclophosphamide via increased glutathione, decreased apoptosis and increased proliferation of intestinal epithelial cells.

Santos GW (1990) Bone marrow transplantation in hematologic malignancies. Current status. Cancer 65(3 Suppl):786–791PubMedCrossRef

Daniele B, Secondulfo M, De Vivo R, Pignata S, De Magistris L, Delrio P, Palaia R, Barletta E, Tambaro R, Carratu R (2001) Effect of chemotherapy with 5-fluorouracil on intestinal permeability and absorption in patients with advanced colorectal cancer. J Clin Gastroenterol 32(3):228–230PubMedCrossRef

Duncan M, Grant G (2003) Oral and intestinal mucositis—causes and possible treatments. Aliment Pharmacol Ther 18(9):853–874PubMedCrossRef

Duggan C, Gannon J, Walker WA (2002) Protective nutrients and functional foods for the gastrointestinal tract. Am J Clin Nutr 75(5):789–808PubMed

Oehler R, Roth E (2003) Regulative capacity of glutamine. Curr Opin Clin Nutr Metab Care 6(3):277–282PubMed

Ziegler TR, Mantell MP, Chow JC, Rombeau JL, Smith RJ (1996) Gut adaptation and the insulin-like growth factor system: regulation by glutamine and igf-i administration. Am J Physiol 271(5 Pt 1):G866–G875

Anderson PM, Schroeder G, Skubitz KM (1998) Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer 83(7):1433–1439PubMedCrossRef

Daniele B, Perrone F, Gallo C, Pignata S, De Martino S, De Vivo R, Barletta E, Tambaro R, Abbiati R, D’Agostino L (2001) Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial. Gut 48(1):28–33PubMedCrossRef

Neu J, DeMarco V, Li N (2002) Glutamine: clinical applications and mechanisms of action. Curr Opin Clin Nutr Metab Care 5(1):69–75PubMedCrossRef

10.

Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ, Klenk DC (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150(1):76–85PubMedCrossRef

11.

Song D, Shi B, Xue H, Li Y, Yang X, Yu B, Xu Z, Liu F, Li J (2006) Confirmation and prevention of intestinal barrier dysfunction and bacterial translocation caused by methotrexate. Dig Dis Sci 51(9):1549–1556PubMedCrossRef

12.

Paulus SC, van Saene HK, Hemsworth S, Hughes J, Ng A, Pizer BL (2005) A prospective study of septicaemia on a paediatric oncology unit: a three-year experience at The Royal Liverpool Children’s Hospital, Alder Hey, UK. Eur J Cancer 41(14):2132–2140PubMedCrossRef

13.

Clavijo J, Gomez-de-Segura IA, Gomez-Garcia L, Vallejo-Cremades MT, Sanchez M, de Miguel E (2004) Growth hormone protects the intestines but not the tumour from 5-fluorouracil toxicity in the short term in the rat. Eur J Gastroenterol Hepatol 16(1):75–82PubMedCrossRef

14.

Kucuk C, Ozkan M, Akgun H, Muhtaroglu S, Sozuer E (2005) The effect of granulocyte macrophage-colony stimulating factor on bacterial translocation after administration of 5-fluorouracil in rats. J Surg Res 128(1):15–20PubMedCrossRef

15.

Nose S, Wasa M, Tazuke Y, Owari M, Fukuzawa M (2010) Cisplatin upregulates glutamine transport in human intestinal epithelial cells: the protective mechanism of glutamine on intestinal mucosa after chemotherapy. JPEN J Parenter Enteral Nutr 34(5):530–537

16.

Arrick BA, Nathan CF (1984) Glutathione metabolism as a determinant of therapeutic efficacy: a review. Cancer Res 44(10):4224–4232PubMed

17.

Mitchell JB, Russo A (1987) The role of glutathione in radiation and drug induced cytotoxicity. Br J Cancer Suppl 8:96–104PubMed

18.

Russo A, Carmichael J, Friedman N, DeGraff W, Tochner Z, Glatstein E, Mitchell JB (1986) The roles of intracellular glutathione in antineoplastic chemotherapy. Int J Radiat Oncol Biol Phys 12(8):1347–1354PubMedCrossRef

19.

Rabik CA, Dolan ME (2007) Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev 33(1):9–23PubMedCrossRef

20.

Hong RW, Rounds JD, Helton WS, Robinson MK, Wilmore DW (1992) Glutamine preserves liver glutathione after lethal hepatic injury. Ann Surg 215(2):114–119PubMedCrossRef

21.

Tazuke Y, Wasa M, Shimizu Y, Wang HS, Okada A (2003) Alanyl-glutamine-supplemented parenteral nutrition prevents intestinal ischemia–reperfusion injury in rats. JPEN J Parenter Enteral Nutr 27(2):110–115PubMedCrossRef

22.

Satoh J, Tsujikawa T, Fujiyama Y, Bamba T (2003) Nutritional benefits of enteral alanyl-glutamine supplementation on rat small intestinal damage induced by cyclophosphamide. J Gastroenterol Hepatol 18(6):719–725PubMedCrossRef

23.

Cerchietti LC, Navigante AH, Lutteral MA, Castro MA, Kirchuk R, Bonomi M, Cabalar ME, Roth B, Negretti G, Sheinker B, Uchima P (2006) Double-blinded, placebo-controlled trial on intravenous l-alanyl-l-glutamine in the incidence of oral mucositis following chemoradiotherapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys 65(5):1330–1337PubMedCrossRef

Title: Glutamine prevents intestinal mucosal injury induced by cyclophosphamide in rats
Authors: Mitsugu Owari
Masafumi Wasa
Takaharu Oue
Satoko Nose
Masahiro Fukuzawa
Publication date: 01-03-2012
Publisher: Springer-Verlag
Published in: Pediatric Surgery International / Issue 3/2012
Print ISSN: 0179-0358
Electronic ISSN: 1437-9813
DOI: https://doi.org/10.1007/s00383-011-3023-0

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Glutamine prevents intestinal mucosal injury induced by cyclophosphamide in rats

Abstract

Purpose

Method

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Method

Results

Conclusions

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