Zanco Journal of Medical Sciences
Skip Navigation Links
Available Issues
Editorial Board
Information for Authors
Review Process
Links and Contacts
  Zanko J Med Sci:  Apr. 2017; 21 (1): 1552-1560

Evaluation of the effect of chamomile extract on lingual histological changes in rabbit received 5-fluorouracil (histological and immunohistochemical study)

Shukria Muhammed Zahawi & Ali Sultan Al-Refai & Hanan Abdulla Abdulqader


Background and objective: Chamomile has been used as an herbal medication since ancient times and is still popular until today. This study aimed to investigate the potential anticytotoxic effect of chamomile extract on the lingual mucosa of rabbits treated with 5-fluorouracil (5-FU).  

Methods: Thirty six rabbits were used in the study. For induction of tongue mucositis for the study group, 5-FU at a dose of (4 mg/kg) was administered intraperitoneally one time daily for five successive days. The control animals were intraperitoneally injected by normal saline one time daily for five successive days. The rats in each group were randomly divided into two groups: Distilled water and chamomile extract treated groups (9 animals each). A volume of distilled water equal to chamomile extract was given by gavage tube, while the other group was gavaged with chamomile extract at a dose of (100 mg/ kg) one time daily. The treatment with distilled water or the chamomile extract was continued for sixteen days and then the animals were sacrificed, and the tongues were excised for histopathological and immunohistochemical analysis.   

Results: The 5-FU/water treated group showed a significant increase in histological damage scores, decrease in the ki-67and increase in caspase -3 epithelial immune expression (P <0.05) in comparison with saline/water treated group. The 5-FU/chamomile treated group showed a significant increase in damage score, significant decrease in ki-67 immune expression and significant increase in caspase-3 immune expression (P <0.05) in comparison with 5-FU/water treated group.   

Conclusion: Chamomile extract at a dose of (100 mg/ kg) one time daily for sixteen days cannot be used for the treatment of oral mucositis. It causes damage to the tissue, decreases proliferation, and increases apoptosis.

Keywords: Lingual papillae; Chamomile; 5-FU; Ki-67; Caspase- 3.


1. Ghom AG, Jedhe SM. Text book of oral pathology. 2nd ed. New Delhi; Jaypee Brothers Medical Publishers; 2013.

2. 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.

3. Noordhuis P, Holwerda U, Van der Wilt CL, Van Groeningen CJ, Smid K, Meijer S, et al. 5-Fluorouracil incorporation into RNA and DNA in relation to thymidylate synthase inhibition of human colorectal cancers. Ann Oncol 2004; 15:1025–32.

4. Mead GM. Management of oral mucositis associated with cancer chemotherapy. Lancet 2002; 359(23):815–6.

5. Chen P, Lingen M, Sonis ST, Walsh-Reitz MM, Toback FG. Role of AMP-18 in oral mucositis. Oral Oncol 2011; 47(9):831–9.  

6. 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.

7. Srivastava JK, Eswar-Shankar E, Gupta S. Chamomile: A herbal medicine of the past with bright future. Mol Med Rep 2010; 3(6):895–901.

8. Al- Bahtiti NH. Chemical analysis and biological activity of Jordanian chamomile extracts. Adv J Food Sci Technol 2012; 4(1):22–5.

9. Svenningsen AB, Madsen KD, Liljefors T, Stafford GI, Van Staden J, Jäger AK. Biflavones from Rhus species with affinity for the GABA (A) benzodiazepine receptor. J Ethno pharmacol 2006; 103(2):276–80.

10. Srivastava JK, Gupta S. Antiproliferative and apoptotic effects of chamomile extract in various human cancer cells. J Agric Food Chem 2007; 55:9470–8. 

11. Ferreira RJ, Carvalho AE, Souza W, Alvarenga FB, Rodrigues FB. Anatomia da Artéria Lingual Profunda em Sus scrofa domestica, LINNAEUS, 1758. Ciência Animal Brasileira 2011; 12(2): 298–305.

12. Miyawaki Y,Yoshimura K, Shindo J, Kageyama I. Light and scanning electron microscopic study on the tongue and lingual papillae of the common raccoon, Procyon lotor. Okajimas Folia Anatomica Japonica 2010; 87(2):65–73. 

13. Fonseca ET, Oliveira CM, Franciolli ALR, Miglino MA. “Caracteristicas das papilas do dorso da lingua de cabras (Capra hircus): estudo por de microscopia eletrônica de varredura e luz. Pesquisa Veterinária Brasileira 2011; 31(1): 67–73.

14. Zheng J, Kobayashi K. “Comparative morphological study on the lingual papillae and their connective tissue cores (CTC) in reeves' muntjac deer (Muntiacus reevesi),” Ann Anat 2006; 188(6):555–64. 

15. Cooper LS, Gillett CE, Smith P, Fentiman IS, Barnes DM. Cell proliferation measured by MIB1 and timing of surgery for breast cancer. Br J Cancer 1998; 77:1502–7.

16. Ermiah E, Buhmeida A, Abdalla F, Khalid BR,Salem N, Pyrhonen S. Prognostic Value of Proliferation Markers: Immunohistochemical Ki-67 Expression and Cytometric S-Phase Fraction of Women with Breast Cancer in Libya. J Cancer 2012; 3:421–31. 

17. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science 2004; 305: 626–9.

18. Decker P, Muller S. Modulating poly (ADP-ribose) polymerase activity: potential for the prevention and therapy of pathogenic situations involving DNA damage and oxidative stress. Curr Pharm Biotechnol 2002; 3:275–83.

19. Degterev A, Boyce M, Yuan J. A decade of caspases. Oncogene 2003; 22:8543–67.

20. Emam MAL. Comparative evaluation of antidiabetic activity of Rosmarinus officinalis and Chamomile recutita in streptozotocin induced diabetic rats. Agric Biol J N Am 2012; 3:247–52.

21. Ozel O, Aycicek A, Kenar F, Aktepe F, Sargin R, Deniz M, et al.  Histopathologic changes in the rabbit submandibular gland after5-fluorouracil chemotherapy. Turk J Med Sci 2010; 40:213–20.

22. Barakat SA. The possible role of green tea in protecting submandibular salivary gland function in rats receiving 5-Fluorouracil 2014. M.Sc. Thesis. Mansoura University, Egypt.

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

24. 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.

25. Christopher AS, Mary JK: Biology of oral mucosa and esophagus. J Natl Cancer Inst Monogr 2001; 29:7–15.

26. Zheng WK, Inokuchi A, Yamamoto T, Komiyama S. Taste dysfunction in irradiated patients with head and neck cancer. Fukuoka Igaku Zasshi 2002; 93(4):64–76.

27. Alvariño-Martín C, Sarrión-Pérez MG. Prevention and treatment of oral mucositis in patients receiving chemotherapy. J Clin Exp Dent 2014; 6(1):74–80.

28. López BC. Oral toxicity produced by chemotherapy: A systematic review. J Clin Exp Dent 2014; 6(1):81–90.

29. Sonis ST. Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 1998; 34(1):39–43.

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

31. Wright TH, Yazbeck R, Lymn KA, Whitford EJ, Cheah KY, Butler RN, et al. The herbal extract, Iberogast, improves jejunal integrity in rats with 5-Fluorouracil (5-FU)-induced mucositis. Cancer Biol Ther 2009; 8:923–9.

32. Pritchard DM, Watson AJ, Potten CS, Jackman AL, Hickman JA. Inhibition by uridine but not thymidine of p53 dependent intestinal apoptosis initiated by 5-fluorouracil: Evidence for the involvement of RNA perturbation. Proc Nat Acad Sci 1997; 94(5):1795–9.

33. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science 2004; 305: 626–9.

34. Carl W, Emrich LS. Management of oral mucositis during local radiation and systemic chemotherapy: a study of 98 patients. J Prosthet Dent 1991; 66:361–9.

35. Fidler PLoprinzi CLO'Fallon JRLeitch JMLee JKHayes DL, et al. Prospective evaluation of chamomile mouth wash for prevention of 5-FU induced mucositis. Cancer 1996; 77(3):552–5.

36. Al-Refai AS. Immunohistochemical study of the effect of chamomile extract on 5-fluorouracil induced intestinal mucositis in albino rats. J Clin Cell Immunol 2014; 5:1–10.

37. Zadeh JB, Moradi Kor N, Moradi Kor Z. Chamomile (Matricaria recutita as a valuable medicinal plant. IJABBR 2014; 2(3):823–9.

38. Cavalieri E, Rigo A, Bonifacio M, Carcereri de Prati A, Guardalben E, Faculi M, et al. Pro- apoptotic activity of α-bisabolol in preclinical models of primary human acute leukemia cells. J Transl Med 2011; 9:45–51.

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.