Inhibitory Effect of Tyrosine Kinase Inhibitors on Antigen-Induced Tracheal Contraction and Histamine Release in Guinea Pigs

1996 ◽  
Vol 111 (3) ◽  
pp. 291-298
Author(s):  
Hajime Iwagoe ◽  
Hirotsugu Kohrogi ◽  
Kazuhiko Fujii ◽  
Junji Hamamoto ◽  
Nahomi Hirata ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Histamine Release ◽  
Tyrosine Kinase Inhibitors ◽  
Guinea Pigs ◽  
Kinase Inhibitors ◽  
Inhibitory Effect

In vitro Measurement and In vivo Prediction of Time-Dependent Inhibitory Effects of Three Tyrosine Kinase Inhibitors on CYP3A Activity

2021 ◽  
Vol 22 ◽  
Author(s):  
Liyan Wang ◽  
Tingting Zhao ◽  
Yunxiang Wang ◽  
Banglian Hu ◽  
Jianfei Tao ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Cyp3a Activity ◽  
Drug Drug Interaction ◽  
Inhibitory Potential

Background: Imatinib, sunitinib, and gefitinib are the three most common tyrosine kinase inhibitors (TKIs). However, their quantitative drug-drug interaction potentials In vivo and the relationship between their structure and inhibitory activity remain unknown. Objective: This study aimed to investigate the potential drug-drug interaction risk of three TKIs based on CYP3A. Methods: 6β-Hydroxylated testosterone formation was selected to probe the CYP3A activity in human liver microsomes. Molecular docking simulation was performed to explore the potential structural alerts. Results: Imatinib exhibited the strongest inhibitory effect towards CYP3A, while the inhibitory potential of gefitinib and sunitinib were comparable to each other but weaker than imatinib. IC50 shift assays demonstrated that the inhibitory potential of all three TKIs was significantly increased after a 30-min preincubation with NADPH. The KI and Kinact values of imatinib, sunitinib, and gefitinib were 3.75 μM and 0.055 min–1, 1.96 μM and 0.037 min–1, and 9.94 μM and 0.031 min–1, respectively. IVIVE results showed that there was a 1.3- to 43.1-fold increase in the AUC of CYP3A-metabolizing drugs in the presence of the TKIs. Conclusion: All three TKIs exhibited a typical irreversible inhibitory effect towards CYP3A. The presence of more N-heterocycles and the resulting better binding confirmation of imatinib may have been responsible for its stronger inhibitory effect than sunitinib and gefitinib. Therefore, caution should be taken when CYP3A-metabolizing drugs are co-administrated with imatinib, sunitinib, or gefitinib.

scholarly journals Inhibitory Effect of Cytoprotective Autophagy Against the Anticancer Activity of Tyrosine Kinase Inhibitors

2020 ◽  
Vol 16 (4) ◽  
pp. 184-185
Author(s):  
Wataru Nakajima ◽  
Shinji Nakamichi ◽  
Hidenori Suzuki ◽  
Nobuyuki Tanaka
Keyword(s):  
Tyrosine Kinase ◽  
Anticancer Activity ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Inhibitory Effect

Efficacy of Tyrosine Kinase Inhibitors in Polycythemia Vera.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2696-2696 ◽  
Author(s):  
Amos S. Gaikwad ◽  
Josef T. Prchal
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Jak2 V617f ◽  
Inhibitory Effect ◽  
Myeloproliferative Disorder ◽  
Wild Type ◽  
Growth Inhibitory ◽  
Hel Cells

The seminal discovery of the Bcr-Abl tyrosine kinase inhibitor, imatinib, has revolutionized the therapy of a clonal myeloproliferative disorder, chronic myeloid leukemia (CML). Polycythemia vera (PV) is also a clonal myeloproliferative disorder due to an acquired mutation of hematopoietic stem cells. The majority of PV patients have a somatic mutation of the Janus 2 tyrosine kinase (JAK2 V617F). This provides an excellent clinical opportunity for development of novel tyrosine kinase inhibitors. We studied the efficacy of tyrosine kinase inhibitors in PV and showed a limited effect of imatinib in vitro and in vivo (Gaikwad et al, Blood106: 2601, 2005). Here, we report on the effect of two tyrosine kinase inhibitors, AEE788 and AMN107 (Novartis Pharma) on PV. AEE788 causes growth arrest and apoptosis via inhibition of multiple receptor kinases, including EGFR, HER-2 and VEGFR, which are known to stimulate tumor cell growth and angiogenesis. AMN107 targets Bcr-Abl, KIT, and PDGFR and has potent activity (30 times) even against mutated Bcr-Abl variants that are resistant to imatinib. We used mouse FDCP reporter cells expressing either the wild-type JAK2 (JAK2 cells) or the mutant JAK2 V617F protein (V617F cells) to examine the growth inhibitory activity of these drugs. AEE788 specifically inhibited the growth of V617F cells at an IC50 of 1μM with no effect on wild type JAK2 cells. We also tested the effect of AEE788 on human erythroleukemic cells (HEL) that carry the JAK2 V617F mutation. AEE788 markedly inhibited the growth of HEL cells with an IC50 ~0.8μM. In contrast, AMN107 showed only marginal growth inhibition on V617F cells (IC50 of 12μM) and on HEL cells (IC50 of 8μM). The effect of AMN107 was similar to imatinib activity, wherein only high concentrations of imatinib (IC50 of 5μM) would inhibit the V617F cells, in contrast to imatinib’s known growth inhibitory effect at lower concentrations on the Bcr-Abl carrying cells (Sun X et al Blood 97, 2008Sun X et al Blood 97, 2001). This data suggest that the tyrosine kinase inhibitors that target Bcr-Abl kinase may not be suitable for treating PV. We then tested the combination of AMN107 and AEE788 but did not observe synergistic effect at varying concentrations on reporter cells. The potent activity of AEE788 on JAK2 V617F suggests that AEE788 may act on unique target(s). We observed a decrease in Heat Shock Protein70 (HSP70) upon AEE788 treatment in HEL cells. Elevated levels of HSP70 are associated with drug resistance and poor prognosis (Creagh EM et al, Leukemia14: 1161, 2000). Down-regulation of HSP70 by anti-sense (Nylandsted et al, PNAS97:7871, 2000) and other interventions (Gaikwad A et al, Clin. Cancer Res 11: 1953Gaikwad A et al, Clin. Cancer Res 11: 2005) show the ability to overcome apoptotic resistance. Furthermore, AEE788 showed a specific inhibitory effect on native PV cells when we used in vitro expanded erythroid progenitors from PV patients. These treated PV expanded cells also showed down-regulation of HSP70. We conclude that AEE788 should be explored for the therapeutic trials of PV.

Side effects of tyrosine kinase inhibitors (TKIs) on bone remodelling

2012 ◽  
Vol 224 (03) ◽  
Author(s):  
JT Tauer ◽  
A Ulmer ◽  
LC Hofbauer ◽  
M Suttorp
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Bone Remodelling

A framework for risk stratification in EGFR+ lung adenocarcinoma treated with tyrosine kinase inhibitors

2019 ◽  
Author(s):  
P Christopoulos ◽  
M Kirchner ◽  
F Bozorgmehr ◽  
N Magios ◽  
AL Volckmar ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Tyrosine Kinase ◽  
Lung Adenocarcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors
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