scholarly journals Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes

2020 ◽  
Vol 21 (5) ◽  
pp. 1672 ◽  
Author(s):  
Wei-Ting Chang ◽  
Ping-Yen Liu ◽  
Kaisen Lee ◽  
Yin-Hsun Feng ◽  
Sheng-Nan Wu
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Ionic Current ◽  
Small Animal ◽  
Ionic Currents ◽  
Neonatal Rat ◽  
Delayed Rectifier ◽  
Qtc Prolongation ◽  
The Impact

Lapatinib (LAP) and sorafenib (SOR) are multitargeted tyrosine kinase inhibitors (TKIs) with antineoplastic properties. In clinical observations, LAP and SOR may contribute to QTc prolongation, but the detailed mechanism for this has been largely unexplored. In this study, we investigated whether LAP and SOR affect the activities of membrane ion channels. Using a small animal model and primary cardiomyocytes, we studied the impact of LAP and SOR on Na+ and K+ currents. We found that LAP-induced QTc prolongation in mice was reversed by isoproterenol. LAP or SOR suppressed the amplitude of the slowly activating delayed-rectifier K+ current (IK(S)) in H9c2 cells in a time- and concentration-dependent fashion. The LAP-mediated inhibition of IK(S) was reversed by adding isoproterenol or meclofenamic acid, but not by adding diazoxide. The steady-state activation curve of IK(S) during exposure to LAP or SOR was shifted toward a less negative potential, with no change in the gating charge required to activate the current. LAP shortened the recovery from IK(S) deactivation. As rapid repetitive stimuli, the IK(S) amplitude decreased; however; the LAP-induced inhibition of IK(S) remained effective. LAP or SOR alone also suppressed inwardly rectifying K+ and voltage-gated Na+ current in neonatal rat ventricular myocytes. The inhibition of ionic currents during exposure to TKIs could be an important mechanism underlying changes in QTc intervals.

scholarly journals The impact of introducing tyrosine kinase inhibitors on chronic myeloid leukemia survival: a population-based study

BMC Cancer ◽  
2018 ◽  
Vol 18 (1) ◽  
Author(s):  
Enza Di Felice ◽  
Francesca Roncaglia ◽  
Francesco Venturelli ◽  
Lucia Mangone ◽  
Stefano Luminari ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Population Based ◽  
Population Based Study ◽  
The Impact

scholarly journals Risk of QTc prolongation among cancer patients treated with tyrosine kinase inhibitors

2020 ◽  
Vol 147 (11) ◽  
pp. 3160-3167 ◽  
Author(s):  
Anan A. Abu Rmilah ◽  
Grace Lin ◽  
Kebede H. Begna ◽  
Paul A. Friedman ◽  
Joerg Herrmann
Keyword(s):  
Tyrosine Kinase ◽  
Cancer Patients ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Qtc Prolongation

scholarly journals The impact of traveling distance to the hospital in cases of treatment using EGFR tyrosine kinase inhibitors

2016 ◽  
Vol 27 ◽  
pp. vii96
Author(s):  
Taichi Miyawaki ◽  
Shigehiro Yagishita ◽  
Mitsuhiro Hujii ◽  
Ai Nakamura ◽  
Naohisa Matsumoto ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
The Impact

scholarly journals PF401 IMMUNE SYSTEM AND CHRONIC MYELOID LEUKEMIA: THE IMPACT OF TYROSINE KINASE INHIBITORS

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 152-153
Author(s):  
R.S. Alves ◽  
S.E. McArdle ◽  
J. Vadakekolathu ◽  
A.C. Gonçalves ◽  
P. Freitas-Tavares ◽  
...  
Keyword(s):  
Immune System ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
The Impact

The impact of concomitant use of tyrosine kinase inhibitors and proton pump inhibitors on survival in older adults with cancer.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e18732-e18732
Author(s):  
Manvi Sharma ◽  
Holly Michelle Holmes ◽  
Hemalkumar B Mehta ◽  
Hua Chen ◽  
Rajender R Aparasu ◽  
...  
Keyword(s):  
Older Adults ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Kinase Inhibitors ◽  
The Impact

Risk of QTc interval prolongation among cancer patients treated with tyrosine kinase inhibitors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3033-3033
Author(s):  
Anan Abdelmoti Abu Rmilah ◽  
Grace Lin ◽  
Joerg Herrmann
Keyword(s):  
Tyrosine Kinase ◽  
Cancer Patients ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Complication Rates ◽  
Qtc Interval ◽  
Interval Prolongation ◽  
Qtc Prolongation ◽  
Qtc Interval Prolongation ◽  
Life Threatening

3033 Background: QTc interval prolongation can lead to life-threatening complications such as torsade de pointes (TdP), ventricular tachycardia (VT), and sudden cardiac death (SCD). It can occur with various tyrosine kinase inhibitors (TKIs) but comparative analyses on the incidence and complication rates are scarce. We thus conducted a comprehensive analysis of TKI use and QTc prolongation in clinical practice. Methods: We retrospectively reviewed the electronic medical records of all cancer patients who were treated with TKI between 01/2005 and 12/2018 at our institution. QTc prolongation was defined as a QTc ≥ 450 ms or 460 ms among male or female patients, respectively. For each type of TKIs, we determined the administration rate and incidence of QTc interval prolongation. We also studied the frequency of QTc prolongation ≥ 500 ms, rate of increase of the QTc interval by ≥ 60 ms, and the development of complications (VT, TdP and SCD). Results: In the present study, we analyzed the data of 685 cancer patients (431 male and 254 female), including 299 patients with RCC, 188 with chronic leukemia, 55 with acute leukemia, 65 with thyroid cancer, 48 with lung cancer and 39 with GIST. These patients received 902 TKI administrations and QTc prolongation was reported in 1/3 of these (289 administrations). The highest frequency was seen with imatinib, nilotinib and dasatinib (30, 40 and 50%). Among cases of QTc prolongation, a QTc interval ≥ 500 ms was documented in 53 (18.3%) and QTc progression ≥ 60 ms in 72 (25%). Complications were found in 14 cases (5%) including VT in 9, TdP in 2 and SCD in 3 administrations. Conclusions: The current findings suggest that TKI therapy leads to QTc prolongation in 1/3 of patients on average and most commonly with the Bcr-Abl TKIs, imatinib, nilotinib and dasatinib. While SCD is rare (1%) it can still evolve and in 5% of all QTc prolongations with TKIs are potentially life-threatening. These data support recommendations for serial ECGs in cancer patients undergoing TKI therapy. [Table: see text]

scholarly journals A population-based study examining the effect of tyrosine kinase inhibitors on survival in metastatic renal cell carcinoma in Alberta and the role of nephrectomy prior to treatment

2013 ◽  
Vol 3 (4) ◽  
pp. 281 ◽  
Author(s):  
Mark Warren ◽  
Peter M. Venner ◽  
Scott North ◽  
Tina Cheng ◽  
Chris Venner ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Population Based ◽  
First Line ◽  
Line Setting ◽  
The Impact

Background: We performed a retrospective population-based studyto assess the impact of tyrosine kinase inhibitors (TKIs) on overallsurvival (OS) in patients treated for metastatic renal cell carcinoma(mRCC) in Alberta, Canada and to assess the impact of nephrectomyon OS in patients treated with TKIs.Methods: We identified 134 patients who began taking a TKIbetween December 2003 and June 2007 for mRCC in Alberta. Wecompared survival in this group to that in an earlier cohort of141 pa tients treated with interferon-α (IFN-α) between May 1995and March 2003. We used the Kaplan–Meier method to determineOS, and we used a Cox proportional hazards model to determinehazard ratios (HRs) and confidence intervals (CIs). We performedmultivariate analysis to assess the impact of neprhectomy on OS.Results: Of the 134 patients treated with TKIs, 81 received treatmentin the first-line setting, whereas 53 received treatment after priorIFN-α therapy. All 141 patients from the IFN-α cohort receivedtreatment in the first-line setting. Patients treated with TKIs had animproved OS compared with the IFN-α cohort (HR 0.61, 95% CI0.45–0.83, p = 0.001). The median OS was 18 months in the TKIgroup and 10 months in the IFN-α group. The benefit of TKIs wasconfined to favourable and intermediate risk groups according tothe Memorial Sloan-Kettering Cancer Center prognostic model.Prior nephrectomy was associated with improved OS in the TKIcohort, independent of other prognostic factors.Conclusion: Tyrosine kinase inhibitors improve OS compared withIFN-α in mRCC. In patients treated with TKIs, prior nephrectomyis associated with improved survival independent of other prognosticvariables.Contexte : Une étude rétrospective de population a été menée afind’évaluer l’effet des inhibiteurs de la tyrosine-kinase (ITK) sur lasurvie globale (SG) des patients atteints d’un néphrocarcinomemétastatique et d’évaluer l’impact d’une néphrectomie sur la SGdes patients traités par ITK.Méthodes : Cent trente-quatre patients en Alberta ont entrepris untraitement par ITK entre decembre 2003 et juin 2007 en raisond’un néphrocarcinome. On a comparé les taux de survie dans cegroupe avec ceux d’un groupe de 141 patients ayant entrepris untraitement de première intention par IFN-α entre mai 1995 et mars2003. La survie globale a été calculée à l’aide de la méthode deKaplan Meier, et le risque relatif (RR) et les intervalles de confiance(IC) ont été calculés à l’aide du modèle des risques proportionnelsde Cox. Une analyse multivariée a permis d’évaluer l’impact dela néphrectomie sur la SG dans la population globale de l’étuded’une part et chez les patients traités par ITK d’autre part.Résultats : Les 134 patients ayant entrepris un traitement par ITK ontété répartis ainsi : traitement de première intention, 81 patients, ettraitement de seconde intention après un traitement par IFN-α,53 patients. Les patients traités par ITK ont montré une SG supérieurepar rapport aux patients traités par IFN-α (RR 0,61, IC à 95 % 0,45–0,83, p = 0,001). La SG médiane était de 18 mois chez les patientstraités par ITK et de 10 mois chez les patients traités par IFN-α. Letraitement par ITK n’a eu un avantage que chez les patients atteintsde néphrocarcinome métastatique présentant un risque faible ouintermédiaire selon le modèle du Memorial Sloan-Kettering CancerCener. Une néphrectomie antérieure a été associée à une meilleureSG dans la cohorte traitée par ITK, indépendamment des autres facteurspronostics.Conclusion : Le traitement par ITK a amélioré la SG par rapport autraitement par IFN-α dans une population « réelle ». Une néphrectomieantérieure a été associée à une SG supérieure chez lespatients traités par ITK.

scholarly journals Impact of Additional Chromosomal Abnormalities in Philadelphia-Positive Clone on Prognosis of CML Patients Treated with Tyrosine Kinase Inhibitors

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1926-1926 ◽  
Author(s):  
Bingcheng Liu ◽  
Ying Wang ◽  
Hui Wei ◽  
Kaiqi Liu ◽  
Dong Lin ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Median Time ◽  
Kinase Inhibitors ◽  
Chromosomal Abnormalities ◽  
Myelogenous Leukemia ◽  
Positive Clone ◽  
Free Survival ◽  
Additional Chromosomal Abnormalities ◽  
The Impact

Abstract Background: To investigate the impact of additional chromosomal abnormalities(ACA) in Philadelphia-positive clone on response to TKIs and long-term survival of CML patients treated with tyrosine kinase inhibitors (TKIs) in the real world. Methods:In this retrospective study, patients with chronic myelogenous leukemia (CML) in chronic phase treated with TKIs were recruited. The chromosome banding analysis was performed on bone marrow cells at baseline and during the TKIs therapy.The clinic response to TKIs was evaluated according to the recommendation of ELN2013. The overall survival (OS), events free survival (EFS) and progression free survival (PFS) were analyzed. Events were defined as treatment failure, progression to accelerate phase or blast crisis and death. The progression was defined according to criteria of ELN2013 CML recommendation. Results: The characters and cytogenetic analysis of the patients:A total of 451 patients (281 males and 170 females) were enrolled from Jun 2004 to March 2015.The median age was 42 (range 18-79) years old. 414 subjects hadevaluable information of karyotypeat baseline.351 patients (84.4%) had the standard Philadelphia chromosome (Ph), 8(1.9%) showed variant translocation of Ph, 19 had ACA in Ph+ cells (Ph+ACA), only 2(0.5%) showed ACA in Ph- cells (Ph-ACA)£¬11(2.7%) had normal karyotype. 29 patients (6.4%) developed Ph+ACA during the TKIs treatment. Ph-ACA occurred in 8 subjects (6.4%).The response to TKIs: Comparing to the patients without Ph+ACA at baseline, the patients with Ph+ACA had lower cumulative rate of complete cytogenetic response (CCyR) (92.4% vs 68.4%, P=0.038) and prolonger median time to achieving CCyR (19 vs 7 months, P=0.016).The Ph+ACA at diagnosis had no effect on achieving major molecular response (MMR). The OS, EFS and PFS at 7 years for the whole cohort were 91%¡¢54% and 83% respectively. The patients with baseline Ph+ACA had significant inferior survival comparing to the subjects without Ph+ACA (Figure 1). The median time of OS, EFS, PFS for Ph+ACA patients were 108, 50 and 91 months, whereas the patients without Ph+ACA were not reached ( P=0.003 for OS, P<0.001 for EFS, and P=0.004 for PFS). The patients developed Ph+ACA during treatment had similar OS comparing to the subjects with Ph-ACA or without ACA (P=0.115), but they had significant shorter EFS (31 vs 90 months vs not reached£¬P<0.001)and PFS(59 vs 120 months vs not reached£¬P<0.001). Conclusion: The Ph+ACA emergence at diagnosis and during treatment had negative impact on prognosis of CML patients treated with TKIs. Disclosures No relevant conflicts of interest to declare.

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