A New Therapeutic Approach to Treat Oral Mucositis Using Specific MMP Blockers in an Osmotically Active Solution

Ravi Shrivastava^, and Swity Deshmukh

Cite this paper:
Ravi Shrivastava and Swity Deshmukh. A New Therapeutic Approach to Treat Oral Mucositis Using Specific MMP Blockers in an Osmotically Active Solution. Journal of Cancer Research and Treatment. 2013; 1(1):4-11. doi: 10.12691/jcrt-1-1-2

Abstract

Mucositis is a consequence of cytostatic effects of anticancer therapy on the fast growing oral mucosal cells. The size of the ulcer increases due to subsequent bacterial and fungal growth, while the leakage of circulating toxins through damaged capillaries surrounding the ulcers causes severe irritation and burning sensation. Proteolytic enzymes, which are known to destroy cellular matrix, inhibit cell regeneration and healing. We tested OROSOL®, an osmotically active hypertonic solution containing specific protease-inhibiting plant procyanidins capable of cleaning the injury, removing the contaminants and stimulating cell growth as a new multiple therapeutic approach for the treatment of mucositis. Out of 69 total patients, 48 were treated with OROSOL® spray, 4-5 times per day for a period of 28 days. 21 patients in the classical treatment group used standard treatments. The grade of overall mucositis, intensity of pain and burning sensation, formation of new ulcers and effect on eating impairment were evaluated before treatment, 30 minutes after first product application and on days 1, 2, 3, 4, 7, 14, 21 and 28. Data were analyzed using SAS 9.1.3. Statistical program. Compared to the classical treatments group, Orosol® group showed significantly higher improvement in pain, burning sensation, eating abilities, grade of infection and overall mucositis. New ulcer formation rate was not affected. Mucositis treatment requires a multiple therapeutic approach of simultaneously eliminating the contaminants and the toxic chemicals from the ulcer as well as creating a favorable ground for healthy cell growth. OROSOL® seems highly effective in achieving these objectives.

Keywords:
mucositis extra cellular matrix (ECM) matrix metalloproteases (MMPs) procyanidins (PCDs) tannins hypertonic

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Figures

References:

[1]	Feller L, Essop R, Wood NH, Khammissa RA, Chikte UM, Meyerov R, Lemmer J. “Chemotherapy- and radiotherapy-induced oral mucositis: pathobiology, epidemiology and management.” SADJ. 65(8):372-4. 2010.
[2]	Vélez I, Tamara LA, Mintz S. “Management of oral mucositis induced by chemotherapy and radiotherapy: an update.” Quintessence Int. 35(2):129-36. Feb 2004.
[3]	Yager DR, Nwomeh BC. “The proteolytic environment of chronic wounds.” Wound Repair Regen. 7(6):433-41. Nov-Dec 1999.
[4]	Strek M, Gorlach S, Podsedek A, Sosnowska D, Koziolkiewicz M, Hrabec Z, Hrabec E. “Procyanidin oligomers from Japanese quince (Chaenomeles japonica) fruit inhibit activity of MMP-2 and MMP-9 metalloproteinases.” J Agric Food Chem. 55(16):6447-52. Aug 2007.
[5]	Lee KW, Kang NJ, Oak MH, Hwang MK, Kim JH, Schini-Kerth VB, Lee HJ. “Cocoa procyanidins inhibit expression and activation of MMP-2 in vascular smooth muscle cells by direct inhibition of MEK and MT1-MMP activities.” Cardiovasc Res. 79(1):34-41. Jul 2008.
[6]	Shrivastava R. “Clinical evidence to demonstrate that simultaneous growth of epithelial and fibroblast cells is essential for deep wound healing.” Diabetes Res Clin Pract. 92(1): 92-9. Apr.2011.
[7]	Shrivastava R. “Non-solid composition for local application.” Patent PCT/FR99/01340, International publication N°WO 00/74668 A1 on 14/12/2000.
[8]	Giner-Chavez BI, Van Soest PJ, Robertson JB, Lascano C, Reed JD, Pell AN. “A method for isolating condensed tannins from crude plant extracts with trivalent Ytterbium.” J. Sci. Food Agric. 74: 359-368. 1997.
[9]	Sonis ST. “Oral mucositis in cancer therapy.” J Support Oncol. 2(6 Suppl 3): 3-8. 2004.
[10]	Sonis ST. (2009) “Mucositis: The impact, biology and therapeutic opportunities of oral mucositis.” Oral Oncol. 45(12):1015-20. 2009.
[11]	Trengove NJ, Stacey MC, MacAuley S, Bennett N, Gibson J, Burslem F, Murphy G, Schultz G. “Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors.” Wound Repair Regen. 7(6):442-52. 1999.
[12]	Rayment EA, Upton Z. “Finding the culprit: a review of the influences of proteases on the chronic wound environment” Int J Low Extrem Wounds. 8(1):19-27. 2009.
[13]	Armstrong DG, Jude EB. “The role of matrix metalloproteinases in wound healing.” J Am Podiatr Med Assoc. 92(1):12-8. 2002.
[14]	Al-Dasooqi N, Gibson RJ, Bowen JM, Keefe DM. “Matrix metalloproteinases: key regulators in the pathogenesis of chemotherapy-induced mucositis?” Cancer Chemother Pharmacol. 64(1):1-9. Jun 2009.
[15]	Al-Dasooqi N, Gibson RJ, Bowen JM, Logan RM, Stringer AM, Keefe DM. (2010) “Matrix metalloproteinases are possible mediators for the development of alimentary tract mucositis in the dark agouti rat.” Exp Biol Med (Maywood) 235(10):1244-56. Oct 2010.
[16]	Leblond J, Le Pessot F, Hubert-Buron A, Duclos C, Vuichoud J, Faure M, Breuillé D, Déchelotte P, Coëffier M. “Chemotherapy-induced mucositis is associated with changes in proteolytic pathways.” Exp Biol Med (Maywood) 233(2): 219-28. 2008.
[17]	Morvan FO, Baroukh B, Ledoux D, Caruelle JP, Barritault D, Godeau G, Saffar JL. “An engineered biopolymer prevents mucositis induced by 5-fluorouracil in hamsters.” Am J Pathol. 164(2):739-46. 2004.
[18]	Zhang H, Chang M, Hansen CN, D. Basso M, Noble-Haeusslein LJ. “Role of Matrix Metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury.” Neurotherapeutics 8(2): 206-20. 2011.
[19]	Gonçalves R, Mateus N, de Freitas V. “Biological relevance of the interaction between procyanidins and trypsin: a multitechnique approach.” J Agric Food Chem. 58(22):11924-31. 2010.
[20]	Jackson JK, Zhao J, Wong W, Burt HM. “The inhibition of collagenase induced degradation of collagen by the galloyl-containing polyphenols tannic acid, epigallocatechin gallate and epicatechin gallate.” J Mater Sci Mater Med. 21(5):1435-43. 2010.
[21]	Déziel BA, Patel K, Neto C, Gottschall-Pass K, Hurta RA. “Proanthocyanidins from the American Cranberry (Vaccinium macrocarpon) inhibit matrix metalloproteinase-2 and matrix metalloproteinase-9 activity in human prostate cancer cells via alterations in multiple cellular signalling pathways.” J Cell Biochem. 111(3): 742-54. 2010.
[22]	Bodet C, Grenier D, Chandad F, Ofek I, Steinberg D, Weiss EI. “Potential oral health benefits of cranberry.” Crit Rev Food Sci Nutr. 48(7): 672-80. 2008.
[23]	Bodet C, Chandad F, Grenier D. “Inhibition of host extracellular matrix destructive enzyme production and activity by a high-molecular-weight cranberry fraction.” J Periodontal Res. 42(2): 159-68. 2007.
[24]	Nishizuka T, Fujita Y, Sato Y, Nakano A, Kakino A, Ohshima S, Kanda T, Yoshimoto R, Sawamura T. “Procyanidins are potent inhibitors of LOX-1: a new player in the French Paradox.” Proc Jpn Acad Ser B Phys Biol Sci. 87(3): 104-13. 2011.