Oral mucositis is the most common and dose-limiting complication of cancer treatment. N-acetylcysteine (NAC) is an antioxidant that minimizes oxidative stress and the lipid peroxidation of cellular membranes. Objective: The present study aimed to evaluate the effects of NAC as a treatment for 5-fluorouracil-induced oral mucositis in hamsters. Methods: The animals were divided into two groups: therapeutic NAC (group I; n = 15) and control group (group II; n = 15). Mucositis was induced in hamsters by intraperitoneal injection of 5-fluorouracil on days 0 and 2, and the left cheek pouch was irritated by superficial scratching on days 3 and 4. In group I, oral mucositis was induced and treated with NAC intraperitoneal infusion during seven days. In group II, mucositis was induced, and no treatment was done. Oral mucosa was photographed from days 4 and 7. Photographs were randomly scored according to the severity of induced mucositis (0 to 5). Excisional biopsies of the palatal mucosa were performed, and the hamsters were sacrificed. Tissue sections were evaluated for morphological and histological analysis. Samples of cheek pouches were removed from animals per group for Malondialdehyde (MDA) measurement. Results: Group I showed better prevention of oral mucosa structural damage than group II. Clinical evaluation demonstrated that group I had a better outcome and faster healing. Group I presented more granulation tissue and fibroblasts. According to Malondialdehyde values, group I showed a decrease in lipid peroxidation. Conclusions: The results suggest that NAC treatment had a positive effect in reducing mucositis severity and a pronounced effect in treating established mucositis.
References
[1]
Lalla, R.V. and Peterson, D.E. (2005) Oral Mucositis. Dental Clinics of North America, 49, 167-184. https://doi.org/10.1016/j.cden.2004.07.009
[2]
Treister, N. and Sonis, S. (2007) Mucositis: Biology and Management. Current Opinion in Otolaryngology & Head & Neck Surgery, 15, 123-129. https://doi.org/10.1097/moo.0b013e3280523ad6
[3]
Kantarjian, H.M. and De Lima, M. (2017) Oral Mucositis in Cancer Therapy: Advances and Challenges. Journal of Clinical Oncology, 35, 2058-2066.
[4]
Cavanagh, J. and Williams, H. (2019) Sodium Bicarbonate Mouthwash as a Strategy for Prevention of Oral Mucositis in Chemotherapy Patients: A Systematic Review. European Journal of Cancer Care, 28, e13041.
[5]
Lalla, R.V., Sonis, S.T. and Peterson, D.E. (2008) Management of Oral Mucositis in Patients Who Have Cancer. Dental Clinics of North America, 52, 61-77. https://doi.org/10.1016/j.cden.2007.10.002
[6]
Sonis, S.T. (2004) The Biology of Mucositis. Supportive Care in Cancer, 12, 670-676.
[7]
Vadhan-Raj, S. and Kuehn, N. (2003) Palifermin Reduces the Incidence and Duration of Severe Oral Mucositis in Patients Undergoing High-Dose Chemotherapy and Radiation Therapy. Blood, 101, 589-598.
[8]
Lalla, R.V., et al. (2014) Palifermin for the Prevention of Oral Mucositis in Patients with Hematological Malignancies. The New England Journal of Medicine, 370, 245-254.
[9]
Sonis, S.T. (2007) Pathobiology of Oral Mucositis: Novel Insights and Opportunities. Journal of Supportive Oncology, 5, 3-11.
[10]
Sonis, S.T., Elting, L.S., Keefe, D., Peterson, D.E., Schubert, M., Hauer-Jensen, M., et al. (2004) Perspectives on Cancer Therapy-Induced Mucosal Injury: Pathogenesis, Measurement, Epidemiology, and Consequences for Patients. Cancer, 100, 1995-2025. https://doi.org/10.1002/cncr.20162
[11]
Sonis, S.T. (2004) A Biological Approach to Mucositis. Journal of Supportive Oncology, 2, 21-32.
[12]
Wadleigh, R.G., Redman, R.S., Graham, M.L., Krasnow, S.H., Anderson, A. and Cohen, M.H. (1992) Vitamin E in the Treatment of Chemotherapy-Induced Mucositis. The American Journal of Medicine, 92, 481-484. https://doi.org/10.1016/0002-9343(92)90744-v
[13]
Mills, E. (1988) The Modifying Effect of Beta-Carotene on Radiation and Chemotherapy Induced Oral Mucositis. British Journal of Cancer, 57, 416-417. https://doi.org/10.1038/bjc.1988.94
[14]
Jahangard-Rafsanjani, Z., Gholami, K., Hadjibabaie, M., Shamshiri, A.R., Alimoghadam, K., Sarayani, A., et al. (2013) The Efficacy of Selenium in Prevention of Oral Mucositis in Patients Undergoing Hematopoietic SCT: A Randomized Clinical Trial. Bone Marrow Transplantation, 48, 832-836. https://doi.org/10.1038/bmt.2012.250
[15]
Ertekin, M.V., Koç, M., Karslioǧlu, I. and Sezen, O. (2004) Zinc Sulfate in the Prevention of Radiation-Induced Oropharyngeal Mucositis: A Prospective, Placebo-Controlled, Randomized Study. International Journal of Radiation OncologyBiologyPhysics, 58, 167-174. https://doi.org/10.1016/s0360-3016(03)01562-1
[16]
De Flora, S., Grassi, C. and Carati, L. (1997) Attenuation of Influenza-Like Symptomatology and Improvement of Cell-Mediated Immunity with Long-Term N-Acetylcysteine Treatment. European Respiratory Journal, 10, 1535-1541. https://doi.org/10.1183/09031936.97.10071535
[17]
Butterfield, D.A., Pocernich, C.B. and Drake, J. (2002) Elevated Glutathione as a Therapeutic Strategy in Alzheimer’s Disease. Drug Development Research, 56, 428-437. https://doi.org/10.1002/ddr.10095
[18]
Blankenberg, S., Rupprecht, H.J., Bickel, C., Torzewski, M., Hafner, G., Tiret, L., et al. (2003) Glutathione Peroxidase 1 Activity and Cardiovascular Events in Patients with Coronary Artery Disease. New England Journal of Medicine, 349, 1605-1613. https://doi.org/10.1056/nejmoa030535
[19]
Miyazono, Y., Gao, F. and Horie, T. (2004) Oxidative Stress Contributes to Methotrexate-Induced Small Intestinal Toxicity in Rats. Scandinavian Journal of Gastroenterology, 39, 1119-1127. https://doi.org/10.1080/00365520410003605
[20]
Oka, S., Kamata, H., Kamata, K., Yagisawa, H. and Hirata, H. (2000) N‐Acetylcysteine Suppresses TNF-Induced NF‐κB Activation through Inhibition of IκB Kinases. FEBS Letters, 472, 196-202. https://doi.org/10.1016/s0014-5793(00)01464-2
[21]
Sonis, S.T., Tracey, C., Shklar, G., Jenson, J. and Florine, D. (1990) An Animal Model for Mucositis Induced by Cancer Chemotherapy. Oral Surgery, Oral Medicine, Oral Pathology, 69, 437-443. https://doi.org/10.1016/0030-4220(90)90376-4
[22]
Sonis, S. (2000) Defining Mechanisms of Action of Interleukin-11 on the Progression of Radiation-Induced Oral Mucositis in Hamsters. Oral Oncology, 36, 373-381. https://doi.org/10.1016/s1368-8375(00)00012-9
[23]
Lopes, N.N.F., Plapler, H., Chavantes, M.C., Lalla, R.V., Yoshimura, E.M. and Alves, M.T.S. (2009) Cyclooxygenase-2 and Vascular Endothelial Growth Factor Expression in 5-Fluorouracil-Induced Oral Mucositis in Hamsters: Evaluation of Two Low-Intensity Laser Protocols. Supportive Care in Cancer, 17, 1409-1415. https://doi.org/10.1007/s00520-009-0603-9
[24]
Jacob, T., Ascher, E., Hingorani, A. and Kallakuri, S. (2003) Glycine Prevents the Induction of Apoptosis Attributed to Mesenteric Ischemia/Reperfusion Injury in a Rat Model. Surgery, 134, 457-466. https://doi.org/10.1067/s0039-6060(03)00164-8
[25]
Okur, H., Küçükaydin, M., Köse, K., Kontaş, O., Doǧan, P. and Kazez, A. (1995) Hypoxia-Induced Necrotizing Enterocolitis in the Immature Rat: The Role of Lipid Peroxidation and Management by Vitamin E. Journal of Pediatric Surgery, 30, 1416-1419. https://doi.org/10.1016/0022-3468(95)90395-x
[26]
Kohn, H.I. and Liversedge, M. (1944) On a New Aerobic Metabolite Whose Production by Brain Is Inhibited by Apomorphine, Emetine, Ergotamine, Epinephrine, and Menadione. The Journal of Pharmacology and Experimental Therapeutics, 82, 292-300. https://doi.org/10.1016/s0022-3565(25)08738-5
[27]
Sonis, S. (2010) New Thoughts on the Initiation of Mucositis. Oral Diseases, 16, 597-600. https://doi.org/10.1111/j.1601-0825.2010.01681.x
[28]
Sonis, S.T. (2004) The Pathobiology of Mucositis. Nature Reviews Cancer, 4, 277-284. https://doi.org/10.1038/nrc1318
[29]
Logan, R.M., Gibson, R.J., Sonis, S.T. and Keefe, D.M.K. (2007) Nuclear Factor-κB (NF-κB) and Cyclooxygenase-2 (COX-2) Expression in the Oral Mucosa Following Cancer Chemotherapy. Oral Oncology, 43, 395-401. https://doi.org/10.1016/j.oraloncology.2006.04.011
[30]
Yeoh, A.S.J., Gibson, R.J., Yeoh, E.E.K., Bowen, J.M., Stringer, A.M., Giam, K.A., et al. (2007) A Novel Animal Model to Investigate Fractionated Radiotherapy-Induced Alimentary Mucositis: The Role of Apoptosis, P53, Nuclear Factor-κB, COX-1, and COX-2. Molecular Cancer Therapeutics, 6, 2319-2327. https://doi.org/10.1158/1535-7163.mct-07-0113
[31]
Kuenen, B.C., Levi, M., Meijers, J.C.M., van Hinsbergh, V.W.M., Berkhof, J., Kakkar, A.K., et al. (2003) Potential Role of Platelets in Endothelial Damage Observed during Treatment with Cisplatin, Gemcitabine, and the Angiogenesis Inhibitor SU5416. Journal of Clinical Oncology, 21, 2192-2198. https://doi.org/10.1200/jco.2003.08.046
[32]
M Logan, R., M Stringer, A., M Bowen, J., J Gibson, R., T Sonis, S. and M K Keefe, D. (2008) Serum Levels of NF-κB and Pro-Inflammatory Cytokines Following Administration of Mucotoxic Drugs. Cancer Biology & Therapy, 7, 1139-1145. https://doi.org/10.4161/cbt.7.7.6207
[33]
Fuchs, B.C. and Bode, B.P. (2006) The Molecular Mechanisms of 5-Fluorouracil-Induced Toxicity. Journal of Clinical Oncology, 24, 3928-3936.
[34]
Zafarullah, M., Li, W.Q., Sylvester, J. and Ahmad, M. (2003) Molecular Mechanisms of N-Acetylcysteine Actions. Cellular and Molecular Life Sciences (CMLS), 60, 6-20. https://doi.org/10.1007/s000180300001
[35]
Sheng-Tanner, X., Bump, E.A. and Hedley, D.W. (1998) An Oxidative Stress-Mediated Death Pathway in Irradiated Human Leukemia Cells Mapped Using Multilaser Flow Cytometry. Radiation Research, 150, 636-647. https://doi.org/10.2307/3579886
[36]
Papi, A. and Conti, A. (2008) The Role of N-Acetylcysteine as an Antioxidant and Anti-Inflammatory Agent in COPD. Pulmonary Pharmacology & Therapeutics, 21, 728-738.
[37]
Mocatta, T., Angelkovska, T., et al. (2020) N-Acetylcysteine as a Preventive Agent against Oxidative Stress and Inflammation in Diseases. Molecular Nutrition & Food Research, 64, e1900779.
[38]
Kocyigit, A., Aksu, A., Karabulut, G., et al. (2016). The Impact of N-Acetylcysteine on the Healing of Irradiated Oral Mucosa: A Histopathological Study. Supportive Care in Cancer, 24, 669-676.
[39]
Klaunig, J.E., Wang, Z., Pu, X. and Zhou, S. (2011) Oxidative Stress and Oxidative Damage in Chemical Carcinogenesis. Toxicology and Applied Pharmacology, 254, 86-99. https://doi.org/10.1016/j.taap.2009.11.028
[40]
Sá, O.M.D.S., Lopes, N.N.F., Alves, M.T.S. and Caran, E.M.M. (2018) Effects of Glycine on Collagen, PDGF, and EGF Expression in Model of Oral Mucositis. Nutrients, 10, Article 1485. https://doi.org/10.3390/nu10101485