Pulmonary complications of Bcr-Abl tyrosine kinase inhibitors

2020 ◽  
Vol 56 (4) ◽  
pp. 2000279 ◽  
Author(s):  
Jason Weatherald ◽  
Louise Bondeelle ◽  
Marie-Camille Chaumais ◽  
Christophe Guignabert ◽  
Laurent Savale ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Tyrosine Kinase ◽  
Arterial Hypertension ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Chronic Myelogenous Leukaemia ◽  
Pulmonary Complications ◽  
Myelogenous Leukaemia ◽  
Dependent Manner ◽  
Pulmonary Arterial

Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. Following the success of imatinib, second- and third-generation molecules were developed. Different profiles of kinase inhibition and off-target effects vary between TKIs, which leads to a broad spectrum of potential toxicities.Pulmonary complications are most frequently observed with dasatinib but all other Bcr-Abl TKIs have been implicated. Pleural effusions are the most frequent pulmonary complication of TKIs, usually associated with dasatinib and bosutinib. Pulmonary arterial hypertension is an uncommon but serious complication of dasatinib, which is often reversible upon discontinuation. Bosutinib and ponatinib have also been associated with pulmonary arterial hypertension, while imatinib has not. Rarely, interstitial lung disease has been associated with TKIs, predominantly with imatinib.Mechanistically, dasatinib affects maintenance of normal pulmonary endothelial integrity by generating mitochondrial oxidative stress, inducing endothelial apoptosis and impairing vascular permeability in a dose-dependent manner. The mechanisms underlying other TKI-related complications are largely unknown. Awareness and early diagnosis of the pulmonary complications of Bcr-Abl TKIs is essential given their seriousness, potential reversibility, and impact on future treatment options for the underlying chronic myelogenous leukaemia.

Tyrosine Kinase Inhibitors in Pulmonary Arterial Hypertension: A Double-Edge Sword?

2013 ◽  
Vol 34 (05) ◽  
pp. 714-724 ◽  
Author(s):  
Laurent Godinas ◽  
Christophe Guignabert ◽  
Andrei Seferian ◽  
Frederic Perros ◽  
Emmanuel Bergot ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Tyrosine Kinase ◽  
Arterial Hypertension ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Double Edge ◽  
Double Edge Sword ◽  
Pulmonary Arterial

scholarly journals Incident pulmonary arterial hypertension associated with Bosutinib

2020 ◽  
Vol 10 (3) ◽  
pp. 204589402093691 ◽  
Author(s):  
Shaun Yo ◽  
John Thenganatt ◽  
Jeffrey Lipton ◽  
John Granton
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Arterial Hypertension ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Case Reports ◽  
Drug Induced ◽  
Pulmonary Arterial ◽  
Partial Reversal

Pulmonary arterial hypertension is associated with tyrosine kinase inhibitors used in the treatment of chronic myeloid leukemia. Dasatinib is a known cause of drug-induced pulmonary arterial hypertension. There have been case reports linking Bosutinib with deterioration of pre-existing pulmonary arterial hypertension. Here, we present a case of a 37-year-old woman with chronic myeloid leukemia treated with Bosutinib who was diagnosed with pulmonary arterial hypertension. Prior to Bosutinib, she had received Dasatinib without documented cardiopulmonary toxicity. Withdrawal of Bosutinib led to partial reversal of pulmonary arterial hypertension, and with the addition of pulmonary arterial hypertension-targeted treatment, there was near normalization of hemodynamics.

scholarly journals Tyrosine Kinase Inhibitor–Induced Pulmonary Arterial Hypertension

2018 ◽  
Vol 17 (2) ◽  
pp. 69-74 ◽  
Author(s):  
Mariana Preda ◽  
Andrei Seferian ◽  
Etienne-Marie Jutant ◽  
Marie-Camille Chaumais ◽  
Laurent Savale ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Tyrosine Kinase ◽  
Arterial Hypertension ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Right Heart Failure ◽  
Early Screening ◽  
Persistent Symptoms ◽  
Pulmonary Arterial ◽  
Tki Treatment

The treatment of the malignant hematological diseases has been revolutionized by the use of tyrosine kinase inhibitors (TKI): for example, imatinib in patients with chronic myeloid leukemia. Dasatinib, a second-generation TKI, has been reported to induce severe pulmonary arterial hypertension (PAH). The mechanism of PAH development is presumed to be endothelial cell toxicity through the production of mitochondrial reactive oxygen species. There are other TKIs that are reported to cause PAH, such as: ponatinib, bosutinib, lapatinib, and lorlatinib. The management of PAH due to TKIs primarily involves stopping the TKI treatment, which can lead to clinical and hemodynamic normalization. A third of the patients who develop PAH can have persistent symptoms of dyspnea and right heart failure even after the interruption of the TKIs. For these patients, use of specific PAH treatment is indicated along with close follow-up. In rare cases, TKI-induced PAH can be fatal. Thus, early screening for PAH diagnosis and proper management is required.

scholarly journals Evaluation of the use, effectiveness and safety of tyrosine kinase inhibitors in chronic myelogenous leukaemia in a general university hospital

2018 ◽  
Vol 27 (5) ◽  
pp. 299-301
Author(s):  
Iratxe Marquinez-Alonso ◽  
Vicente Escudero-Vilaplana ◽  
Santiago Osorio ◽  
Carmen G Rodriguez-Gonzalez ◽  
Eva González-Haba ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Chronic Myelogenous Leukaemia ◽  
Myelogenous Leukaemia ◽  
University Hospital

Tyrosine kinase inhibitors enhance GHRH-stimulated cAMP accumulation and GH release in rat anterior pituitary cells

1997 ◽  
Vol 152 (2) ◽  
pp. 193-199 ◽  
Author(s):  
T Ogiwara ◽  
C L Chik ◽  
A K Ho
Keyword(s):  
Tyrosine Kinase ◽  
Cholera Toxin ◽  
Tyrosine Kinase Inhibitors ◽  
Anterior Pituitary ◽  
Kinase Inhibitors ◽  
Pituitary Cells ◽  
Dependent Manner ◽  
Camp Accumulation ◽  
Anterior Pituitary Cells ◽  
Site Of Action

Abstract In this study, the role of tyrosine phosphorylation in agonist-stimulated cAMP accumulation and GH release in rat anterior pituitary cells was investigated. It was found that genistein, a tyrosine kinase inhibitor, while having no effect on its own, potentiated GHRH-stimulated cAMP accumulation in a concentration-dependent manner. In comparison, daidzein, an inactive analogue of genistein, was ineffective and vanadate, a phosphotyrosine phosphatase inhibitor, reduced GHRH-stimulated cAMP accumulation. Additional structurally unrelated tyrosine kinase inhibitors, erbstatin and tyrphostins, also potentiated GHRH-stimulated cAMP accumulation. To determine the site of action of the tyrosine kinase inhibitors, pituitary adenylate cyclase-activating polypeptide (PACAP), cholera toxin and forskolin were used to increase cAMP accumulation. Genistein enhanced the PACAP-, cholera toxin- or forskolin-stimulated cAMP accumulation, suggesting that the site of action is at the post-receptor level. However, when the phosphodiesterase was inhibited by isobutylmethylxanthine, genistein did not potentiate and vanadate did not inhibit GHRH-stimulated cAMP accumulation, indicating that phosphodiesterase is a probable site of action for the inhibitor. Genistein and erbstatin also enhanced GHRH-stimulated GH release and the effect of vanadate was inhibitory. These results indicate that tyrosine kinase inhibitors enhance cAMP accumulation through their action on phosphodiesterase activity in rat anterior pituitary cells and the tyrosine kinase pathway appears to be involved in the control of GH release. Journal of Endocrinology (1997) 152, 193–199

Safflower injection inhibits pulmonary arterial remodeling in a monocrotaline-induced pulmonary arterial hypertension rat model

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Aifeng Chen ◽  
Shibiao Ding ◽  
Liangliang Kong ◽  
Jianpu Xu ◽  
Fei He ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Cardiac Muscle ◽  
Rat Model ◽  
Dependent Manner ◽  
Arterial Remodeling ◽  
Pulmonary Arterial ◽  
Dose Dependent

AbstractPulmonary arterial hypertension (PAH) is a group of diseases with an increase of pulmonary artery pressure (PAP) and pulmonary vascular resistance. Here, the effects of safflower injection, a preparation of Chinese herbs, was investigated in a monocrotaline (MCT)-induced PAH rat model. PAP, carotid artery pressure (CAP), and the right ventricular hypertrophy index (RVHI) increased in the PAH group, while safflower injection was able to inhibit this increase to similar levels as observed in the normal group. The arteriole wall of the lungs and cardiac muscle were thickened and edema was observed in the PAH group, while these pathologies were improved in the herb-treated group in a dose-dependent manner. MCT treatment induced proliferation of pulmonary artery smooth muscle cells (PASMCs), which was inhibited by safflower injection in a dose-dependent manner. Our experimental results demonstrated that safflower injection can regulate pulmonary arterial remodeling through affecting the expression of connective tissue growth factor, transforming growth factor-β, integrin, collagen or fibronectin, which subsequently affected the thicknesses of the arteriole walls of the lungs and cardiac muscle, and thereby benefits the control of PAH. This means safflower injection improved the abnormalities in PAP, CAP and RVHI, and pulmonary arterial remodeling through regulation of remodeling factors.

Tyrosine kinase inhibitors and antioxidants modulate NF-κB and NOS-II induction in retinal epithelial cells

1998 ◽  
Vol 275 (1) ◽  
pp. C208-C215 ◽  
Author(s):  
Violaine Faure ◽  
Yves Courtois ◽  
Olivier Goureau
Keyword(s):  
Epithelial Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Nuclear Translocation ◽  
Pyrrolidine Dithiocarbamate ◽  
Dependent Manner ◽  
Mrna Accumulation ◽  
Ifn Γ

Bovine retinal pigmented epithelial (RPE) cells express an inducible nitric oxide synthase (NOS-II) after activation with interferon-γ (IFN-γ) and lipopolysaccharide (LPS). Experiments were performed to investigate the effects of tyrosine kinase inhibitors (genistein and herbimycin A) and antioxidants [pyrrolidine dithiocarbamate (PDTC) and butyl hydroxyanisol] on NOS-II induction. The LPS-IFN-γ-induced nitrite release was inhibited in a concentration-dependent manner by these compounds. Analysis by Northern blot showed that this inhibitory effect correlated with a decrease in NOS-II mRNA accumulation. Analysis by electrophoretic mobility shift assay of the activation of the transcription factor nuclear factor-κB (NF-κB) involved in NOS-II induction demonstrated that LPS alone or combined with IFN-γ induced NF-κB binding. NF-κB activation was not changed by the presence of tyrosine kinase inhibitors but was totally prevented by PDTC pretreatment. Immunocytochemistry experiments confirmed the reduction of the nuclear translocation of NF-κB only by PDTC. Our results demonstrated the existence in retinal pigmented epithelial cells of different intracellular signaling pathways in NOS-II induction, since tyrosine kinase inhibitors blocked NOS-II mRNA accumulation without inhibiting NF-κB activation. Furthermore, the LPS-IFN-γ-induced NOS-II mRNA accumulation was sensitive to cycloheximide, suggesting that, in addition to NF-κB, transcriptional factors that require new protein synthesis are involved in NOS-II induction.

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