5-Fluorouracil administration using clinical treatment protocol causes mucositis in the ileum in Wistar rats
Keywords:Oxidative stress; Inflammation; Myenteric plexus; Chemotherapy; Cancer.
The present study evaluated the effects of 5-fluorouracil (5-FU) administration using a clinical treatment protocol for 14 days on the ileum in healthy Wistar rats. The animals were divided into two groups (n = 6/group): 5-FU-treated group and control group. The 5-FU group received 5-FU (15 mg/kg, i.p.) for 4 consecutive days, followed by a dose reduction to 6 mg/kg for 4 alternating days and then a last maintenance dose of 15 mg/kg on day 14. This treatment protocol is commonly used in the human clinical setting. The control group received saline (i.p.) according to the same treatment protocol. The ileum was then fractionated to evaluate oxidative stress parameters (catalase [CAT], superoxide dismutase [SOD], glutathione-S-transferase [GST], non-protein sulfhydryl groups [GSH], reactive oxygen species [ROS], and lipid hydroperoxide [LOOH]), markers of inflammation (interleukin-1 [IL-1], IL-6, myeloperoxidase [MPO], and N-acetylglucosaminidase [NAG]), and nitrite levels. HuC/D-immunoreactive myenteric neurons, neuronal nitric oxide synthase (nNOS)-immunoreactive nitrergic neurons, and ileum wall morphometry were also analyzed. The 5-FU treatment protocol promoted oxidative stress and altered nitrite levels but did not cause inflammation. The treatment protocol also reduced the density of nitrergic neurons and altered the morphometry of the general HuC/D-positive myenteric neuronal population and nNOS-positive nitrergic neuronal subpopulation. Treatment with the clinical 5-FU treatment protocol promoted grade I mucositis in rats, characterized by oxidative stress and morphological changes in the intestinal wall.
Aebi, H. (1984). Catalase in Vitro. Methods in Enzymology. https://doi.org/10.1016/S0076-6879(84)05016-3
Birben, E., Sahiner, U. M., Sackesen, C., Erzurum, S., & Kalayci, O. (2012). Oxidative stress and antioxidant defense. In World Allergy Organization Journal. https://doi.org/10.1097/WOX.0b013e3182439613
Brandt, R., & Keston, A. S. (1965). Synthesis of diacetyldichlorofluorescin: A stable reagent for fluorometric analysis. Analytical Biochemistry. https://doi.org/10.1016/0003-2697(65)90035-7
Chang, C. T., Ho, T. Y., Lin, H., Liang, J. A., Huang, H. C., Li, C. C., Lo, H. Y., Wu, S. L., Huang, Y. F., & Hsiang, C. Y. (2012). 5-fluorouracil induced intestinal mucositis via nuclear factor-κB activation by transcriptomic analysis and in vivo bioluminescence imaging. PLoS ONE. https://doi.org/10.1371/journal.pone.0031808
Costa, D. V. S., Bon-Frauches, A. C., Silva, A. M. H. P., Lima-Júnior, R. C. P., Martins, C. S., Leitão, R. F. C., Freitas, G. B., Castelucci, P., Bolick, D. T., Guerrant, R. L., Warren, C. A., Moura-Neto, V., & Brito, G. A. C. (2019). 5-Fluorouracil Induces Enteric Neuron Death and Glial Activation During Intestinal Mucositis via a S100B-RAGE-NFκB-Dependent Pathway. Scientific Reports. https://doi.org/10.1038/s41598-018-36878-z
Cuéllar-Garduño, N. (2015). Interacciones farmacológicas de la quimioterapia y la anestesia. FARMACOLOGÍA EN ANESTESIA, 38(1), S159–S162
El-Sayyad, H. I., Ismail, M. F., Shalaby, F. M., Abou-El-Magd, R. F., Gaur, R. L., Fernando, A., Raj, M. H. G., & Ouhtit, A. (2009). Histopathological effects of cisplatin, doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats. International Journal of Biological Sciences. https://doi.org/10.7150/ijbs.5.466
Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, B. F. (2018). Global Cancer Observatory: Cancer Tomorrow. Lyon, France: International Agency for Research on Cancer. Available from: https://gco.iarc.fr/tomorrow
Gelen, V., Şengül, E., Yıldırım, S., & Atila, G. (2018). The protective effects of naringin against 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats. Iranian Journal of Basic Medical Sciences. https://doi.org/10.22038/ijbms.2018.27510.6714
Harris, D. J. (2006). Cancer treatment-induced mucositis pain: Strategies for assessment and management. In Therapeutics and Clinical Risk Management. https://doi.org/10.2147/tcrm.2006.2.3.251
Jiang, Z. Y., Woollard, A. C. S., & Wolff, S. P. (1991). Lipid hydroperoxide measurement by oxidation of Fe2+ in the presence of xylenol orange. Comparison with the TBA assay and an iodometric method. Lipids. https://doi.org/10.1007/BF02536169
Kang, K. A., Piao, M. J., Kim, K. C., Kang, H. K., Chang, W. Y., Park, I. C., Keum, Y. S., Surh, Y. J., & Hyun, J. W. (2014). Epigenetic modification of Nrf2 in 5-fluorouracil-resistant colon cancer cells: Involvement of TET-dependent DNA demethylation. Cell Death and Disease. https://doi.org/10.1038/cddis.2014.149
Kubes, P., & McCafferty, D. M. (2000). Nitric oxide and intestinal inflammation. In American Journal of Medicine. https://doi.org/10.1016/S0002-9343(00)00480-0
Leocádio, P. C. L., Antunes, M. M., Teixeira, L. G., Leonel, A. J., Alvarez-Leite, J. I., Machado, D. C. C., Generoso, S. V., Cardoso, V. N., & Correia, M. I. T. D. (2015). L-arginine pretreatment reduces intestinal mucositis as induced by 5-FU in mice. Nutrition and Cancer. https://doi.org/10.1080/01635581.2015.1004730
Marklund, S., & Marklund, G. (1974). Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem, 47(3), 469–474. https://www.ncbi.nlm.nih.gov/pubmed/4215654
McManus, J. F. A. (1946). Histological demonstration of mucin after periodic acid . In Nature. https://doi.org/10.1038/158202a0
McQuade, R. M., Stojanovska, V., Donald, E., Abalo, R., Bornstein, J. C., & Nurgali, K. (2016). Gastrointestinal dysfunction and enteric neurotoxicity following treatment with anticancer chemotherapeutic agent 5-fluorouracil. Neurogastroenterology and Motility. https://doi.org/10.1111/nmo.12890
Medeiros, A. da C., Azevedo, Í. M., Lima, M. L., Araújo Filho, I., & Moreira, M. D. (2018). Efeitos da sinvastatina na mucosite gastrointestinal induzida por 5-fluorouracil em ratos. Revista Do Colégio Brasileiro de Cirurgiões, 45(5), 1–8. https://doi.org/10.1590/0100-6991e-20181968
Muthu, R., Thangavel, P., Selvaraj, N., Ramalingam, R., & Vaiyapuri, M. (2013). Synergistic and individual effects of umbelliferone with 5-flurouracil on the status of lipid peroxidation and antioxidant defense against 1, 2-dimethylhydrazine induced rat colon carcinogenesis. Biomedicine and Preventive Nutrition. https://doi.org/10.1016/j.bionut.2012.10.011
Okumura, R., & Takeda, K. (2017). Roles of intestinal epithelial cells in the maintenance of gut homeostasis. In Experimental and Molecular Medicine. https://doi.org/10.1038/emm.2017.20
Prabhu, K. S., Reddy, P. V., Jones, E. C., Liken, A. D., & Reddy, C. C. (2004). Characterization of a class alpha glutathione-S-transferase with glutathione peroxidase activity in human liver microsomes. Archives of Biochemistry and Biophysics. https://doi.org/10.1016/j.abb.2004.02.002
Rivera, L. R., Thacker, M., Pontell, L., Cho, H. J., & Furness, J. B. (2011). Deleterious effects of intestinal ischemia/reperfusion injury in the mouse enteric nervous system are associated with protein nitrosylation. Cell Tissue Res, 344(1), 111–123. https://doi.org/10.1007/s00441-010-1126-x
Rtibi, K., Selmi, S., Grami, D., Amri, M., Sebai, H., & Marzouki, L. (2018). Contribution of oxidative stress in acute intestinal mucositis induced by 5 fluorouracil (5-FU) and its pro-drug capecitabine in rats. Toxicology Mechanisms and Methods. https://doi.org/10.1080/15376516.2017.1402976
Sedlak, J., & Lindsay, R. H. (1968). Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem, 25(1), 192–205. https://www.ncbi.nlm.nih.gov/pubmed/4973948
Shiota, A., Hada, T., Baba, T., Sato, M., Yamanaka-Okumura, H., Yamamoto, H., Taketani, Y., & Takeda, E. (2010). Protective effects of glyco glycerol lipids extracted from spinach on 5-fluorouracil induced intestinal mucosal injury. Journal of Medical Investigation
Sies, H. (1999). Glutathione and its role in cellular functions. Free Radical Biology and Medicine. https://doi.org/10.1016/S0891-5849(99)00177-X
Soares, P. M. G., Mota, J. M. S. C., Gomes, A. S., Oliveira, R. B., Assreuy, A. M. S., Brito, G. A. C., Santos, A. A., Ribeiro, R. A., & Souza, M. H. L. P. (2008). Gastrointestinal dysmotility in 5-fluorouracil-induced intestinal mucositis outlasts inflammatory process resolution. Cancer Chemotherapy and Pharmacology. https://doi.org/10.1007/s00280-008-0715-9
Soares, P. M. G., Mota, J. M. S. C., Souza, E. P., Justino, P. F. C., Franco, A. X., Cunha, F. Q., Ribeiro, R. A., & Souza, M. H. L. P. (2013). Inflammatory intestinal damage induced by 5-fluorouracil requires IL-4. Cytokine. https://doi.org/10.1016/j.cyto.2012.10.003
Sonis, S. T., Elting, L. S., Keefe, D., Peterson, D. E., Schubert, M., Hauer-Jensen, M., Bekele, B. N., Raber-Durlacher, J., Donnelly, J. P., & Rubenstein, E. B. (2004). Perspectives on cancer therapy-induced mucosal injury. Cancer. https://doi.org/10.1002/cncr.20162
Tiwari, V; Kuhad, A; Chopra, K. (2011). Emblica officinalis corrige déficits funcionais, bioquímicos e moleculares na neuropatia diabética experimental, visando a cascata inflamatória mediada pelo estresse oxido-nitrosativo. Phytother. Res, 25, 1527–1536
Warholm, M., Guthenberg, C., von Bahr, C., & Mannervik, B. (1985). Glutathione transferases from human liver. Methods Enzymol, 113, 499–504. https://www.ncbi.nlm.nih.gov/pubmed/3003505
Yasuda, M., Kato, S., Yamanaka, N., Iimori, M., Matsumoto, K., Utsumi, D., Kitahara, Y., Amagase, K., Horie, S., & Takeuchi, K. (2013). 5-HT3 receptor antagonists ameliorate 5-fluorouracilinduced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells. British Journal of Pharmacology. https://doi.org/10.1111/bph.12019
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Copyright (c) 2020 Lilian Catarim Fabiano; Mariana Conceição da Silva; Karile Cristina da Costa ; Pedro Luiz Zonta de Freitas; Camila Quaglio Neves; Stephanie Carvalho Borges; Ana Cristina Breithaupt-Faloppa; Nilza Cristina Buttow
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