ABSTRACT
Conclusion:
It is concluded that, protein-tyrosine kinase inhibitor imatinib may cause dose related degenerative changes in the liver, and liver functions should be monitored in patients during treatment.
Results:
In 10 mg/kg and 50 mg/kg imatinib applied experimental groups, the nuclear and cytoplasmic structures, sinusoidal and perisinusoidal areas were similar to the control group. In 100 mg/kg imatinib applied group cytoplasmic density was increased, lytic areas and lipid accumulation in cytoplasm of some hepatocytes were seen. In 200 mg/kg imatinib applied experimental group lytic changes and lipid accumulation were prominent.
Methods:
200-250 g, 8-12 weeks old, 30 mature male Wistar rats were used. Rats were divided in 5 groups; 10, 50, 100 and 200 mg/kg imatinib daily were administered by gavage during 21 days to the experimental groups respectively. Fifth group was control; saline was given. Serum levels of liver transaminases, bilirubin, alkaline phosphatase were examined, morphological effects were investigated via electron microscopy.
Aim:
Imatinib is a protein tyrosine kinase inhibitor that’s used as an anticancer drug. In this study, evaluation the effects of different doses of imatinib on liver ultrastructurally and biochemically was aimed.
Keywords:
Imatinib, liver, ultrastructure
References
1Capdeville R, Silberman S, Dimitrijevic S. Imatinib: the first 3 years. Eur J Cancer 2002;38:77-82.
2Lyseng-Williamson K, Jarvis B. Imatinib. Drugs 2001;61:1765-74.
3Agrawal M, Garg RJ, Cortes J, Quintás-Cardama A. Tyrosine kinase inhibitors: the first decade. Curr Hematol Malig Rep 2010;5:70-80.
4Moen MD, McKeage K, Plosker GL, Siddiqui MA. Imatinib: a review of its use in chronic myeloid leukaemia. Drugs 2007;67:299-320.
5Hsiao HH, Liu YC, Tsai HJ, et al. Imatinib mesylate therapy in advanced gastrointestinal stromal tumors: experience from a single institute. Kaohsiung J Med Sci 2006;22:599-603.
6An JY, Choi MG, Noh JH, et al. Gastric GIST: a single institutional retrospective experience with surgical treatment for primary disease. Eur J Surg Oncol 2007;33:1030-5.
7Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001;344:1052-6.
8Wang S, Wilkes MC, Leof EB, Hirschberg R. Imatinib mesylate blocks a non-Smad TGF-beta pathway and reduces renal fibrogenesis in vivo. FASEB J 2005;19:1-11.
9Schellings MW, Baumann M, van Leeuwen RE, et al. Imatinib attenuates end-organ damage in hypertensive homozygous TGR(mRen2)27 rats. Hypertension 2006;47:467-74.
10Yoshiji H, Noguchi R, Kuriyama S, et al. Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats. Am J Physiol Gastrointest Liver Physiol 2005;288:907-13.
11Gonzalo T, Beljaars L, van de Bovenkamp M, et al. Local inhibition of liver fibrosis by specific delivery of a platelet-derived growth factor kinase inhibitor to hepatic stellate cells. J Pharmacol Exp Ther 2007;321:856-65.
12Guilhot F. Indications for imatinib mesylate therapy and clinical management. Oncologist 2004;9:271-81.
13Kansu E. Hedeflenmiş tedavilerde “hedef” moleküller. Available from: https://www.kanser.org/saglik/upload/Hedefe_Yonelik_Tedavi_KUrsu/Hedeflenmi%c5%9f_Tedavilerde_Hedef_Molek%c3%bcller%23Emin_Kansu.pdf ANKEM Derg 2005;19(Ek 2):112-6.
14Erdogan A, Özkan A. Moleküler hedefli anti-kanser ajan kombinasyonlarını optimize etmek için stratejiler. Archives Medical Review Journal 2015;24:432-51.
15Üskent N. Hedefe yönelik tedaviler ne kadar isabetli? Onkoloji Bülteni Onkovital 2010;4:1. DOI: 10.17827/aktd.55888
16Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene 2000;19:5548-57.
17Di Gion P, Kanefendt F, Lindauer A, et al. Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on pyrimidines, pyridines and pyrroles. Clin Pharmacokinet 2011;50:551-603.
18Mucke H. The role of imatinib in the treatment of pulmonary hypertension. Drugs Today (Barc) 2013;49:203-11.
19Jang SW, Ihm SH, Choo EH, et al. Imatinib mesylate attenuates myocardial remodeling through inhibition of platelet-derived growth factor and transforming growth factor activation in a rat model of hypertension. Hypertension 2014;63:1228-34.
20Wu TT, Goodarzi H, Wang J, Novoa R, Teng JMC. Imatinib as a potentially effective therapeutic alternative in corticosteroid-resistant eosinophilic fasciitis. Pediatr Dermatol 2020;37:1171-2.
21Cross TJ, Bagot C, Portmann B, Wendon J, Gillett D. Imatinib mesylate as a cause of acute liver failure. Am J Hematol 2006;81:189-92.
22Garcia-Cortes M, Robles-Diaz M, Stephens C, Ortega-Alonso A, Lucena MI, Andrade RJ. Drug induced liver injury: an update. Arch Toxicol 2020;94:3381-407.
23Mihajlovic M, Ivkovic B, Jancic-Stojanovic B, et al. Modulation of oxidative stress/antioxidative defence in human serum treated by four different tyrosine kinase inhibitors. Anticancer Drugs 2020;31:942-9.
24Boyer-Diaz Z, Morata P, Aristu-Zabalza P, Gibert-Ramos A, Bosch J, Gracia-Sancho J. Oxidative Stress in Chronic Liver Disease and Portal Hypertension: Potential of DHA as Nutraceutical. Nutrients 2020;12:2627.
25Ferrero D, Pogliani EM, Rege-Cambrin G, et al. Corticosteroids can reverse severe imatinib-induced hepatotoxicity. Haematologica 2006 ;91:27.
