Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1
5-Year Impact Factor – 2.2
Scopus CiteScore – 3.4 (CiteScore Tracker 3.7)
Index Copernicus  – 161.11; MNiSW – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2018, vol. 27, nr 6, June, p. 715–720

doi: 10.17219/acem/68967

Publication type: original article

Language: English

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Protective effects of tumor necrosis factor alpha inhibitors on methotrexate-induced pancreatic toxicity

Tolga Mercantepe1,A,B,C,D,E, Yıldıray Kalkan1,A,B,C,D,E, Levent Tumkaya1,A,B,C,D,E, İbrahim Sehitoglu2,A,B,C, Filiz Mercantepe3,D,E, Sermet Yıldırmıs4,C

1 Departments of Histology and Embryology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey

2 Department of Pathology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey

3 Department of Internal Medicine, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey

4 Department of Pathology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey

Abstract

Background. Methotrexate (MTX), a folate antagonist, is commonly used in the treatment of many different types of cancer and inflammatory diseases, including pancreatic cancer, although its side effects on the pancreas have not yet been researched. The mechanism of MTX-induced toxicity is not well known, and it has been reported in high-dose toxicity studies that the pancreas is sensitive to toxic effects.
Objectives. The aim of our study was to determine whether adalimumab (ADA) has a preventive effect on MTX-induced pancreas toxicity in rats.
Material and Methods. The rats were equally and randomly divided into 3 groups (Group 1 comprised the healthy controls, Group 2 was the MTX group, and Group 3 was the MTX + ADA group). The rats in Groups 2 and 3 received an intraperitoneal (ip.) single-dose injection of MTX (20 mg/kg). A single dose of 5 mg/kg ADA (REMICADE®) was administered ip. to Group 3. All the rats were sacrificed under anesthesia 5 days after receiving the MTX injection.
Results. Significantly higher mean edema, necrotic cell, and inflammatory scores were recorded in Groups 2 and 3 compared to those recorded in Group 1. Significantly decreased edema, number of necrotic cells, and inflammatory scores were noted in Group 3 than in Group 2. A decrease in islets of Langerhans cell insulin and somatostatin-positive interneurons was demonstrated after the administration of MTX. An increase in insulin and somatostatin-positive cells in islets of Langerhans, as well as a remodeling of the structure of the pancreas, was shown following treatment with ADA.
Conclusion. Adalimumab was demonstrated to have a protective effect against MTX-induced pancreatic injury in this study.

Key words

adalimumab, methotrexate, pancreas, rat, toxicity

References (27)

  1. Sendur N, Karaman G, Savk E, Sahinkarakas E. Cutaneous ulceration as an early manifestation of methotrexate toxicity. T Klin J Med Sci. 2002;22:593–596.
  2. Calvert AH, Walling JM. Clinical studies with MTA. Br J Cancer. 1998;78:35–40.
  3. Selhub J, Dhar GJ, Rosenberg IH. Inhibition of folate enzymes by sulfasalazine. J Clin Invest. 1978;61:221–224.
  4. Behrens F, Canete JD, Olivieri I, van Kuijk AW, McHugh N, Combe B. Tumour necrosis factor inhibitor monotherapy vs combination with Mtx in the treatment of PsA: A systematic review of the literature. Rheumatology. 2015;54:915–926.
  5. Cure E, Kirbas A, Tumkaya L, et al. Protective effect of infliximab on methotrexate-induced liver injury in rats: Unexpected drug interaction. J Cancer Res Ther. 2015;11:164–169.
  6. Moghadam AR, Tutunchi S, Namvaran-Abbas-Abad A, et al. Pre-administration of turmeric prevents methotrexate-induced liver toxicity and oxidative stress. BMC Complement Altern Med. 2015;15:246.
  7. Kanter M, Yuncu M. Protective effects of vitamin E against methotrexate-induced mucosal damage of the small intestine in mice: An electron microscopic study. TAD Journal. 2006;4:1–6.
  8. Güzel R. Rheumatoid arthritis and disease modifying antirheumatic drugs. Turk J Phys Med Rehab. 2008;54:25–30.
  9. Salzer WL, Devidas M, Shuster JJ, et al. Intensified PEG-L-asparaginase and antimetabolite-based therapy for treatment of higher risk precursor-B acute lymphoblastic leukemia: A report from the Children’s Oncology Group. J Pediatr Hematol Oncol. 2007;29:369-375.
  10. Lipsky PE, van der Heijde DM, St. Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med. 2000;30:1594–1602.
  11. Harriman G, Harper LK, Schaible TF. Summary of clinical trials in rheumatoid arthritis using infliximab, an anti-TNFÆ treatment. Ann Rheum Dis. 1999;58:161–164. doi:10.1056/NEJM200011303432202
  12. Goto Y, Yue L, Yokoi A, et al. A novel single-nucleotide polymorphism in the 3*-untranslated region of the human dihydrofolate reductase gene with enhanced expression. Clin Cancer Res. 2001;7:1952–1956.
  13. Schmiegel W, Roeder C, Schmielau J, Rodeck U, Kalthoff H. Tumor necrosis factor alpha induces the expression of transforming growth factor alpha and the epidermal growth factor receptor in human pancreatic cancer cells. Proc Natl Acad Sci. 1993;90:863–867.
  14. Schmidt J, Rattner DW, Lewandrowski K, et al. A better model of acute pancreatitis for evaluating therapy. Ann Surg. 1992;215:44–56.
  15. Tinder TL, Subramani DB, Basu GD, et al. MUC1 enhances tumour progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma. J Immunol. 2008;181:3116–3125.
  16. Gokalp O, Karakoyun I, Kaleli S, Ozer MK, Gultekin F. The effects of chlorpyrifos-ethyl on pancreas in rats. Journal of Suleyman Demirel University Medicine. 2005;12:19–22.
  17. Gardi JE, Nyengaard JR, Gundersen HJ. Automatic sampling for unbiased and efficient stereological estimation using the proportionator in biological studies. J Microsc. 2005;230:108–120.
  18. Maruyama H, Nakatsuji N, Sugihara S, et al. Anaplastic Ki-1-positive large cell lymphoma of the pancreas: A case report and review of the literature. Jpn J Clin Oncol. 1997;27:51–57.
  19. Tasaka Y, Nakaya F, Matsumoto H, Omori Y. Effects of aminoguanidine on insulin release from pancreatic islets. Endocr J. 1994;41:309–313.
  20. Hiramatsu S, Inoue K, Sako Y, Umeda F, Nawata H. Secretion of insulin and glucagon by the perfused pancreas of genetically obese (fa/fa) Zucker rats and its alteration with aging. Endocr J. 1995;42:563–567.
  21. Kimura N, Schindler M, Kasai N, Kimura I. Immunohistochemical localization of somatostatin receptor type 2A in rat and human tissues. Endocr J. 2001;48:95–102.
  22. Tasaka Y, Nakaya H, Omori Y. Effects of aminoguanidine on glucagon and insulin release from rat pancreatic islet. Endocr J. 1996;43:725–730.
  23. Heitz PU, Kasper M, Polak JM, Kloppel G. Pathology of the endocrine pancreas. J Histochem Cytochem. 1979;27:1401–1402.
  24. Sampaio AF, Silva M, Dornas WC, et al. Iron toxicity mediated by oxidative stress enhances tissue damage in an animal model of diabetes. Biometals. 2014;27:349–361.
  25. Kalkan Y, Tumkaya L, Bostan H, et al. Effect of sugammadex on rocuronium induced changes in pancreatic mast cells. Toxicol Ind Health. 2015;31:738–746.
  26. Tanaka T, Sekine A, Tsunoda Y, et al. Central nervous system manifestations of tuberculosis-associated immune reconstitution inflammatory syndrome during adalimumab therapy: A case report and review of the literature. Intern Med. 2005;54:847–851.
  27. Rau R. Adalimumab (a fully human anti-tumour necrosis factor α monoclonal antibody) in the treatment of active rheumatoid arthritis: The initial results of five trials. Ann Rheum Dis. 2002;61:70–73.
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