Chemoprotective effect of ascorbic acid on cyclophosphomide induced oral toxicity

Authors

  • Ali Sultan Al-Refai Department of Oral and Maxillofacial Surgery, College of Dentistry, Hawler Medical University, Erbil, Iraq.

DOI:

https://doi.org/10.15218/zjms.2017.002

Keywords:

Ascorbic acid, Cyclophosphamide, Oral mucositis, Antioxidant, PCNA

Abstract

Background and objective: Oral mucositis is currently considered to be the most severe complication of anticancer therapy such as cyclophosphamide (CTX). Ascorbic acid is a well-known antioxidant, which can protect the body from damage caused by free radicals that can be generated during normal metabolism as well as through exposure to toxins and carcinogens. This study aimed to evaluate the effectiveness of ascorbic acid as a treatment for CTX induced oral mucositis. 

Methods: Forty Wister-albino rats, age about 6-8 weeks and weighing 150-200 g were used. The rats were randomly divided by simple random allocation into two groups (20 animals each). The control group was intraperitoneally injected with physiological saline and the animals were grouped randomly into two groups: Saline/Water treated group which were daily received intraperitoneal injection of distilled water, while the Saline/Ascorbic acid treated group received a daily intraperitoneal injection of ascorbic acid (12mg/kg/day). For the induction of mucositis, a single dose (300 mg/kg) of CTX was administered intraperitoneally to each animal in the study group, and the animals were grouped randomly into two groups: CTX /Water treated group which was daily received intraperitoneal injection of distilled water, while the CTX /Ascorbic acid treated group were daily received intraperitoneal injection of 12 mg/kg /day of ascorbic acid. The animals were sacrificed at day four and eight (five animals each) and the tongue was dissected from the jaw for histological and immunohistochemical analysis.

Results: Ascorbic acid decreased the severity of the induced CTX oral mucositis by a significant increase in epithelial thickness, significant decrease in damage score, and significant increase in PCNA immune expression at day four and eight respectively (P <0.05).  

Conclusion: CTX chemotherapy has a deleterious effect on the oral mucosa leading to marked morphometric and microscopic changes. Ascorbic acid can protect the oral mucosa from CTX-induced cytotoxicity, and attenuate or decrease the associated injury.  

Metrics

Metrics Loading ...

References

Ghom AG, Jedhe SM. Text book of oral pathology. 2nd edition. New Delhi: Jaypee Brothers, Medical Publishers Pvt. Limited; 2013.

Da Cruz Campos MI, Campos CN, Aarestrup FM, Aarestrup JV. Oral Mucositis in cancer treatment: Natural history, prevention and treatment (review). Mol Clin Oncol 2014; 2(3):337–40.

Miller MM, Donald DV, Hagemann TM. Prevention and treatment of oral mucositis in children with cancer. J Pediatr Pharmacol Ther 2012; 17(4): 340–50.

Sonis ST. A biological approach to mucositis. J Support Oncol 2004; 2(1):21–32.

Aras MH, Sezer U, Erkilic S, Demir T, Dagli SN. Effect of dietary boron on 5- fluorouracil induced oral mucositis in rats. Eur J Dent 2013; 7(3):10–4.

Javed A, Ashwini LS, TS, Sagar S, Medam SK. Effect of quercetin on cyclophosphamide induced biochemical profiles in rat liver. Int J Res Stud Biosci 2014; 2:40–6.

Khan S, Jena G. Sodium cylophosphamide-induced genotoxicit and cytotoxicity in the colon of mice. J Basic Clin Physiol Pharmacol 2014; 27:1–11.

Panigrahy SK, Jatawa S, Archana Tiwari A. Therapeutic use of cyclophosphamide and its cytotoxic action : A challenge for researchers. J Pharm Res. 2011; 4(8):2755–7.

Doloff JC, Chen C,David J Waxman DJ. Anti-tumor innate immunity activated by intermittent metronomic cyclophosphamide treatment of brain tumor xenografts is preserved by anti-angiogenic drugs that spare VEGF receptor-2. Mol Cancer 2014; 13:158–71.

Fassbinder T, Saunders U, Mickholz E, Jung E, Becker H, Schlüter B, et al. Differential effects of cyclophosphamide and mycophenolate mofetil on cellular and serological parameters in patients with systemic lupus erythematosus. Arthritis Res Ther 2015; 17:92–114.

Fukazawa M, Kawaguchi H, Shigematsu H, Koga C, Mori E, Nishimura S, et al. High incidence-rate of oral mucositis in breast cancer patients receiving anthracycline-based chemotherapy (FEC100). Jpn J Cancer Chem 2012; 39(3): 395–8.

Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, et al. Mucositis study section of the multinational association of supportive care in cancer and the International Society for Oral Oncology. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 2007; 109(5): 820–31.

Al-Refai AS, Al-Barazenchy H, Khalil A K. Immunohistochemical study of the effect of green tea extract on methotrexate- induced oral mucositis in albino rats. J Cytol Histol 2014; 5(3):1–7.

El-Gendy KS, Aly NM, Mahmoud FH, Kenawy A, El-Sebae AK. The role of vitamin C as antioxidant in protection of oxidative stress induced by imidacloprid. Food Chem. Toxicol 2010; 48:215–21.

Nadia RA, Abou-Zeid. Ameliorative effect of vitamin C against 5-fuorouracil –induced hepatotoxicity in mice: A light and electron microscope study. J Basic Appli Zool 2014; 67:109–18.

Owari M, Wasa M, Oue T, Nose S, Fukuzawa M. Glutamine prevents intestinal mucosal injury induced by cyclophosphamide in rats. Pediatr Surg Int 2012; 28(3):299–303.

Ücuncu H, Ertekin MV, Yoruk Ö, Sezen O, Özkan A, Erdog˘ AN F, et al. Vitamin E and L-carnitine, separately or in combination, in the prevention of radiation-induced oral mucositisband myelosuppression: a controlled study in a rat model. J Radiat Res 2006; 47:91–102.

Seleit IA, Asaad N, Maree A, Abdel Wahed M. Immunohistochemical expression of p53 and Ki-67 in cutaneous lupus erythematosus. J Egypt Women Dermatol Soc 2010; 7(1):5–15.

Sonis ST. Efficacy of palifermin (keratinocyte growth factor-1) in the amelioration of oral mucositis. Core Evid 2010; 4:199–205.

Riordan NH, Riordan HD, Casciari JJ. Clinical and experimental experiences with intravenous vitamin C. J Orthomol Med 2000; 15:201–3.

Riordan HD, Hunninghake RB, Riordan NH, Jackson JJ, Meng X, Taylor P, et al. Intravenous ascorbic acid: protocol for its application and use. P R Health Sci J 2003; 22 (3):287–90.

Sakagami H, Satoh K, Hakeda Y, Kumegawa M. Apoptosis- inducing activity of vitamin C and vitamin K. Cell Mol Biol 2000; 46:129–35.

Kim J, Lee SD, Chang B, Jin DH, Jung S, Park MY, et al. Enhanced antitumor activity of vitamin C via p53 in cancer cells. Free Radic Biol Med 2012; 53(8):1607–15.

Zhao J, Kim KA, De Vera J. Spondin 1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical Wnt/beta-catenin pathway. Proc Natl Acad Sci 2009; 106:2331–6.

Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have cancer. Dent Clin North Am 2008; 52:61–77.

Lima V, Vidal FD, Rocha FA, Brito GA, Ribeiro RA. Effects of tumor necrosis factor-alpha inhibitors pentoxifylline and thalidomide on alveolar bone loss in short-term experimental periodontal disease in rats. J Periodontol 2004; 75:162–8.

Shih A, Miaskowski C, Dodd M, Stotts N, MacPhail L. Mechanisms for radiation-induced oral mucositis and the consequences. Cancer Nurs 2003; 26(3):222–9.

Cawley MM, Benson LM. Current trends in managing oral mucositis. Clin J Oncol Nurs 2005; 9(5):584–92.

Aboushady IM, Mubarak RT,; El-mougy SAF, Rashed LA, El-desouky AA. The effect of transplanted bone marrow Sstem cells on the tongue of irradiated rats (Histological and Immunohistochemical study). J Am Sci 2012; 8(11):553–61.

Jezernik K1, Romih R, Mannherz HG, Koprivec D. Immunohistochemical detection of apoptosis, proliferation and inducible nitric oxide synthase in rat urothelium damaged by cyclophosphamide treatment. Cell Biol Int 2003; 27(10):863–9.

Ratnam DV, Ankola DD, Bhardwaj V, Sahana DK, Ravi Kumar MNV. Role of antioxidants in prophylaxis and therapy: a pharmaceutical perspective. J Control Release 2006; 113(3): 189–207.

Naidu KA. Vitamin C in human health and disease is still a mystery? An overview. Nutr J 2003; 2:7–11.

Mikirova N, Casciari J, Rogers A, Taylor P. Effect of high-dose intravenous vitamin C on inflammation in cancer patients. J Transl Med 2012; 10(1):189–98.

Saeed RW, Peng T, Metz CN. Ascorbic acid blocks the growth inhibitory effect of tumor necrosis factor-alpha on endothelial cells. Exp Biol Med 2003; 228:855–65.

Suhail N, Bilal N, Khan HY, Hasan S, Sharma S, Khan F, et al. Effect of vitamins C and E on antioxidant status of breast-cancer patients undergoing chemotherapy. J Clin Pharm Ther 2012; 37:22–6.

Podmore ID, Griffiths HR, Herbert KE, Mistry N, Mistry P, Lunec J. Vitamin C exhibits pro-oxidant properties. Nature 1998; 392(6676):559–64.

Lee KW, Lee HJ, Surh YJ, Lee CY. Vitamin C and cancer chemoprevention: reappraisal. Am J Clin Nutr 2003; 78(6):1074–8.

Mohan S, Priya V. Changes in lipid peroxidation, glutathione,ascorbic cid, vitamin E and antioxidant enzymes in patients with ovarian cancer. Acta Med Acad 2009: 38(1):1–5.

Downloads

Published

2017-04-12

How to Cite

Al-Refai, A. S. (2017). Chemoprotective effect of ascorbic acid on cyclophosphomide induced oral toxicity. Zanco Journal of Medical Sciences (Zanco J Med Sci), 21(1), 1540–1551. https://doi.org/10.15218/zjms.2017.002

Issue

Section

Original Articles