Glycine supplementation reduces the severity of chemotherapy-induced oral mucositis in hamsters


Objective: Oral mucositis (OM) is a devastating toxicity associated with cytotoxic cancer therapy. The OM pathogenesis and the complex interactions occur in response to tissue insult. Application of this evolving model has aided in the development of mechanistically based therapies for the prevention and treatment of mucositis. The present study was to assess the effects of glycine supplementation on chemotherapy-induced oral mucositis. Methods: In a hamster cheek pouch model of chemotherapy-induced oral mucositis, one group of 20 animals received systemic glycine supplementation for 7 days, while another similar control group did not. Clinical mucositis severity and neutrophil infiltrate (on histology) were assessed by blinded examiners. Free radical production was measured as malondialdehyde (MDA) levels. Results: As compared to control animals, glycine-treated animals demonstrated a highly significant reduction in clinical severity of oral mucositis, neutrophil infiltrate, and MDA levels (p < 0.001 for all). Conclusions: Glycine supplementation reduces the severity of chemotherapy-induced oral mucositis in an animal model. This effect is at least partly mediated through inhibition of the inflammatory response and reduced production of damaging free radicals.

Share and Cite:

Sá, O. , Lopes, N. , Alves, M. , Lalla, R. , Oliva, M. and Caran, E. (2013) Glycine supplementation reduces the severity of chemotherapy-induced oral mucositis in hamsters. Natural Science, 5, 972-978. doi: 10.4236/ns.2013.59118.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Sonis, S.T., Elting, L.S., Keefe, D., Peterson, D.E. and Schubert, M.M. (2004) Perspectives on cancer therapy induced mucosal injury. Cancer, 100, 1005-2025. doi:10.1002/cncr.20162
[2] Rubenstein, E.B., Peterson, D.E., Schubert, M.M., et al. (2004) Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral gastrointestinal mucositis. Cancer, 100, 2026-2046. doi:10.1002/cncr.20163
[3] Lalla, R.V. and Peterson, D.E. (2005) Oral mucositis. Dental Clinics of North America, 49, 167-184. doi:10.1016/j.cden.2004.07.009
[4] Sonis, S.T. (2004) The pathobiology of mucositis. Nature Reviews Cancer, 4, 277-284. doi:10.1038/nrc1318
[5] Sonis, S.T., Oster, G., Fuchs, H., et al. (2001) Oral mu cositis and the clinical and economic outcomes of hema topoetic-stem cells transplantation. Journal of Clinical Oncology, 19, 2201-2205.
[6] Elting, L.S., Keefe, D.M., Sonis, S.T., et al. (2008) Bur den of illness head and neck writing committee. Patient reported measurements of oral mucositis in head and neck cancer patients treated with radiotherapy with or without chemotherapy: Demonstration of increased frequency, severity, resistance to palliation, and impact on quality of life. Cancer, 113, 2704-2713.
[7] Lalla, R.V. (2011) Translating mucositis research from animal models to humans: Challenges and opportunities. The Journal of Supportive Oncology, 9, 169-175. doi:10.1016/j.suponc.2011.04.011
[8] Zanin, T., Zanin, F., Carvalhosa, A.A., Castro, P.H.S., Pacheco, M.T., Zanin, I.C.J., et al. (2010) Use of 660-nm diode laser in prevention and treatment of human oral mucositis induced by radiotherapy and chemotherapy. Photomedicine and Laser Surgery, 28, 233-237. doi:10.1089/pho.2008.2242
[9] Bensadoun, R.J. (2006) Low level laser therapy (LLLT): A new paradigm in themanagement of cancer therapy induced mucositis. Indian Journal of Medical Research, 124, 375-378.
[10] Sonis, S.T. (2010) New thoughts on the initiation of mu cositis. Oral Diseases, 16, 597-600. doi:10.1111/j.1601-0825.2010.01681.x
[11] Haque, J.A., McMahan, R.S., Campbell, J.S., et al. (2011) Attenuated progression of dietinduced steatohepatitis in glutathione-deficient mice. Laboratory Investigation, 90, 1704-1717.
[12] Sonis, S.T. (2002) The biologic role for nuclear factor kappaB in disease and its potential involvement in muco sal injury associated with anti-neoplastic therapy. Critical Reviews in Oral Biology & Medicine, 13, 380-389. doi:10.1177/154411130201300502
[13] Zhong, Z., Wheeler, M.D., Li, X., et al. (2003) L-glycine: A novel anti-inflammatory, immunomodulatory, and cy toprotective agent. Current Opinion in Clinical Nutrition & Metabolic Care, 6, 229-240. doi:10.1097/00075197-200303000-00013
[14] Wheeler, M., Stachlewitz, R.F., Yamashina, S., Ikejima, K., Morrow, A.L. and Thurman, R.G. (2000) Glycinegated chloride channels in neutrophils attenuate calcium influx and superoxide production. FASEB Journal, 14, 476-484.
[15] Qu, W., Ikejima, K, Zhong, Z., Waalkes, M.P. and Thur man, R.G. (2002) Glycine blocks the increase in intracel lular free Ca2 due to vasoactive mediators in hepatic parenchymal cells. American Journal of Physiology Gas trointestinal and Liver Physiology, 283, G1249-G1256.
[16] Bilzer, M., Baron, A., Schauer, R., Steib, C., Ebensberger, S. and Gerbes, A.L. (2002) Glutathione treatment protects the rat liver against injury after warm ischemia and Kup ffer cell activation. Digestion, 66, 49-57. doi:10.1159/000064415
[17] Stoffels, B., Turler, A., Schmidt, J., et al. (2011) Anti inflammatory role of glycine in reducing rodent postop erative inflammatory ileus. Neurogastroenterology & Mo tility, 23, 76-78. doi:10.1111/j.1365-2982.2010.01603.x
[18] Neyrinck, A.M., Margagliotti, S. and Delzenne, N.M. (2005) Insight into the involvement of Kupffer cell-de rived mediators in the hepatoprotective effect of glycine upon inflammation: study on rat precision-cut liver slices. Inflammation Research, 54, 106-112.
[19] Mikalauskas, S., Mikalauskiene, L., Bruns, H., et al. (2011) Dietary glycine protects from chemotherapy-induced he patotoxicity. Amino Acids, 40, 1139-1150. doi:10.1007/s00726-010-0737-6
[20] Jacob, T., Ascher, E., Hingorani, A. and Kallakuri, S. (2003) Glycine prevents the induction of apoptosis attrib uted to mesenteric ichemial-reperfusion injury in a rat model. Surgery, 134, 457-466. doi:10.1067/S0039-6060(03)00164-8
[21] Sonis, S.T., Tracey, C., Shlar, G., Jenson, J., Florine, D. and Almeida, C. (1990) An animal model for mucositis induced by cancer chemotherapy. Oral Surgery, Oral Me dicine, Oral Pathology, 69, 437-443. doi:10.1016/0030-4220(90)90376-4
[22] Sonis, S.T., Peterson, R.L., Edwards, L.J., Lucey, C.A., et al. (2000) Defining mechanisms of action of inter leukin-11 on the progression of radiation-induced oral mucosites in hamsters. Oral Oncology, 36, 373-81. doi:10.1016/S1368-8375(00)00012-9
[23] Lopes, N.N., Plapler, H., Chavantes, M.C., et al. (2010) Cyclooxygenase-2 and vascular endothelial growth factor expression in 5-fluorouracil-induced oral mucositis in hamsters: Evaluation of two low-intensity laser protocols. Support Care Cancer, 7, 1409-1415.
[24] Okur, H., Kücükaydin, M., Kose, K., Kontas, O., Dogan, P. and Kazez, A. (1995) Hypoxia-induced necrotizing en terocolitis in the immature rat: the role of lipid peroxida tion and management by vitamin E. Journal of Pediatric Surgery, 30, 1416-1432. doi:10.1016/0022-3468(95)90395-X
[25] Kohn, H.I. and Liversedge, M. (1994) On a new aerobic metabolite whose production by brain is inhibited by apomorphine, emetine, ergotamine, epinephrine and ma nadione. Journal of Pharmacology and Experimental Therapeutics, 82, 292-300.
[26] Logan, R.M., Gibson, R.J., Sonis, S.T., et al. (2007) Nu clear factorkappaB (NF-happaB) and cycloxygenase-2 (COX-2) expression in oral mucosa following cancer chemotherapy. Oral Oncology, 43, 395-401. doi:10.1016/j.oraloncology.2006.04.011
[27] Yeoh, A.S., Gibson, R.J., Yeoh, E.E., et al. (2007) A novel animal model to investigate fractionated radiotherapy induced alimentary mucositis: The role of apoptosis, p53, nuclear factor-kappaB, COX-1, and COX-2. Molecular Cancer Therapeutics, 6, 2319-2327. doi:10.1158/1535-7163.MCT-07-0113
[28] Kuenen, B.C., Levi, M., Meijers, J.C., et al. (2003) Po tential role of platelets in endothelial damage during treatment with cisplatin-gemcitabine, and the angiogene sis inhibitorSU5416. Journal of Clinical Oncology, 21, 2192-2198. doi:10.1200/JCO.2003.08.046
[29] Logan, R.M., Stringer, A.M., Bowen, J.M., et al. (2008) Serum levels of NF-kB and proinflammatory cytokines following administration of mucotoxic drugs. Cancer Bi ology & Therapy, 7, 1139-1145. doi:10.4161/cbt.7.7.6207
[30] Lalla, R.V., Pilbeam, C.C., Walsh, S.J., et al. (2010) Role of the cyclooxygenase pathway in chemotherapy-induced oral mucositis: A pilot study. Support Care Cancer, 18, 95-103.
[31] Lalla, R.V., Schubert, M.M., Bensadoun, R.J. and Keefe, D, (2006) Anti-inflammatory agents in the management of alimentary mucositis. Support Care Cancer, 14, 558 565. doi:10.1007/s00520-006-0050-9
[32] Froh, M., Thurman, R.G. and Wheeler, M.D. (2002) Mo lecular evidence for a glycine-gated chloride channel in macrophages and leukocytes. American Journal of Physi ology Gastrointestinal and Liver Physiology, 283, G856-G863.
[33] Hartog, A.L. (2007) Anti-inflammatory effects of orally ingested lactoferrin and glycine in different zymosan-in duced inflammation models: Evidence for synergistic ac tivit. International Immunopharmacology, 7, 1784-1792. doi:10.1016/j.intimp.2007.09.019
[34] Wagner, A.F., Frey, M., Neugebauer, F.A., Schafer, W. and Knappe, J. (1992) The free radical in pyruvate for mate-lyase is located on glycine-734. Proceedings of the National Academy of Sciences, 89, 996-1000. doi:10.1073/pnas.89.3.996
[35] Mauriz, B., Matilla, J., Culebras, M., González, P. and González-Gallego, J. (2001) Dietary glycine inhibits ac tivation of nuclear factor kappa B and prevents liver in jury in hemorrhagic shock in the rat. Free Radical Biol ogy & Medicine, 31, 1236-1244. doi:10.1016/S0891-5849(01)00716-X
[36] Rubbo, H., Radi, L., Trugillo, M., et al. (1994) Nitric oxide regulation of superoxide and peroxynitrite-depen dent lipid peroxidation. Formation of novel nitrogen-con taining oxidized lipid derivatives. The Journal of Bio logical Chemistry, 296, 26066-26075.
[37] Radi, R., Beckman, J.S., Bush, K.M., et al. (1991) Per oxynitrite oxidation of sulfhydryls. The cytotoxic poten tial of superoxide and nitric oxide. The Journal of Bio logical Chemistry, 266, 4244-4250.
[38] Beckman, J.S. (1996) Oxidative damage and tyrosine nitration from peroxynitrite. Chemical Research in Toxi cology, 9, 836-844. doi:10.1021/tx9501445
[39] Beckman, J.S. and Koppenol, W.H. (1996) Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and ug ly. American Journal of Physiology, 271, C1424-C1437.
[40] Szabo, C. (1996) The pathophysiological role of peroxy nitrite in shock, inflammation, and ischemia-reperfusion injury. Shock, 6, 79-88. doi:10.1097/00024382-199608000-00001
[41] Li, X., Bradford, B.U., Wheeler, M.D., et al. (2001) Die tary glycine prevents peptidoglycan polysaccharidein duced reactive arthritis in the rat: Role for glycine-gated chloride channel. Infection and Immunity, 69, 5883-5891. doi:10.1128/IAI.69.9.5883-5891.2001
[42] Kallakuri, S., Pagala, M., Gade, P., et al. (2003) Protec tive effect of glycine in mesenteric ischemia and reperfu sion injury in a rat model. Journal of Vascular Surgery, 38, 1113-1120.
[43] Poschl, E., Schlotzer-Schrehardt, U., Brachvogel, B., Saito, K., Ninomiya, Y. and Mayer, U. (2004) Collagen IV is essential for basement membrane stability but dis pensable for initiation of its assembly during early dev elopment. Epub, 131, 1619-1628.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.