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Background: Small-molecule tyrosine kinase inhibitors (TKIs) have had major impacts on anticancer therapy by targeting the catalytic activities of dysregulated tyrosine kinases. TKIs have not presented traditional toxicities; however, some serious adverse effects, including hepatotoxicity, have been documented in clinical trials and post-marketing surveillance. Although TKI-induced hepatotoxicity can cause severe clinical complications in patients, the underlying mechanism is still unclear. Methods: Studies on TKI-induced hepatotoxicity were identified by Pubmed search, and relevant articles were reviewed. Results: Immunoallergic reaction, cytochrome P (CYP) 450 polymorphisms, and formation of reactive metabolites are under consideration as mechanisms of TKI-induced hepatotoxicity. Host protein-drug metabolite conjugates are recognized as antigens by class II major histocompatibility complexes and are believed to cause liver injuries. Polymorphisms in CYP, which influences TKI metabolism, can slow TKI metabolism and may induce development of hepatotoxicity. The formation of reactive metabolites during drug metabolism can induce hepatotoxicity by directly causing cytotoxicity, leading to cell dysfunction, and indirect toxicity by mediating secondary immune reactions. Concurrent use of various medications with TKI can also cause hepatotoxicity by affecting drug transporter or enzyme activities. Conclusion: Periodic monitoring of patients taking TKIs and risk/benefit reassessments though post marketing surveillance are necessary to prevent hepatotoxicity.
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참고문헌 (70)
참고문헌 신청
Krause DS / 2005 / Tyrosine kinases as targets for cancer therapy / N Engl J Med 353(2):172~187
Chen MH / 2008 / Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics / Circulation 118(1):84~95
Orphanos GS / 2009 / Cardiotoxicity induced by tyrosine kinase inhibitors / Acta Oncol 48(7):964~970
Cohen MH / 2002 / Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia / Clin Cancer Res 8(5):935~942
Shah DR / 2013 / Tyrosine kinase inhibitors: their on-target toxicities as potential indicators of efficacy / Drug Saf 36(6):413~426
Chen MH / 2008 / Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics / Circulation 118(1):84~95
Orphanos GS / 2009 / Cardiotoxicity induced by tyrosine kinase inhibitors / Acta Oncol 48(7):964~970
Cohen MH / 2002 / Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia / Clin Cancer Res 8(5):935~942
Shah DR / 2013 / Tyrosine kinase inhibitors: their on-target toxicities as potential indicators of efficacy / Drug Saf 36(6):413~426
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