Preclinical and clinical experience with dasatinib in philadelphia chromosome-negative leukemias and myeloid disorders

Verstovšek, Srđan

doi:10.1016/j.leukres.2008.10.001

Cited by 7 publications

(3 citation statements)

References 79 publications

(91 reference statements)

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“…Results showed dasatinib to induce a greater percentage LDH release in both 2 and 5 µM concentrations tested compared to imatinib; this trends with the relative drug potencies as dasatinib binds about 325 times stronger than imatinib. 15 This mixed view was supported by a later follow-up study using the same neonatal rat cardiomyo-cyte model, again identifying poor selectivity among TKIs as a driver for damage, and also pointing to the potency of on-target ABL1 inhibition as a simultaneous contributor. 16 It has long been theorized that on-target inhibition of the ABL protein can be a cause of TKI-induced cardiotoxicity, when such adverse effects were seen in clinical trials with imatinib.…”

Section: Selected Tkismentioning

confidence: 94%

Mechanisms, monitoring, and management of tyrosine kinase inhibitors-associated cardiovascular toxicities

Chaar

Kamta

Ait‐Oudhia

2018

OTT

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The tyrosine kinase inhibitor (TKI) drug class is a prominently used option in the treatment of various cancers. Safety evaluation of these drugs has shown evidence of cardiotoxicity of varying frequency and severity between agents; concern has led to updated labeling, warning prescribers of such. This review seeks to clarify the present dangers and investigate cardiotoxic mechanisms of action for each discussed TKI. Dasatinib was connected primarily with an incidence of fluid retention, edema, QT prolongation, and pulmonary hypertension in clinical studies. It is theorized that this is due to a combination of off-target kinase binding and on-target binding of Bcr-Abl, and less likely, mitochondrial induced apoptosis. Studies showed sorafenib to carry the risk of hypertension, QT prolongation, and myocardial infarction. Proposed mechanisms for these side effects include inhibition of proteins, vascular endothelium growth factor receptor, hERG potassium channels, and the RAF/MERK/ERK pro-survival pathway. Finally, lapatinib showed evidence of decreased left ventricular ejection fraction (LVEF) and QT prolongation in clinical studies. The literature attributes these as side effects of on-target ErbB2 binding leading to mitochondrial induced apoptosis. The concern warranted by these findings is in question. Pooled safety data suggest that the overall risk for cardiotoxicity is minimal in dasatinib and lapatinib. Sorafenib seems to carry a moderate concern. For the discussed agents, recommendations agree that routine monitoring via methods such as electroencephalogram, cardiac biomarkers, and blood pressure is warranted during the course of treatment, in addition to a comprehensive collection of past medical history and risk factors to identify those at heightened risk for cardiovascular events.

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Section: Selected Tkismentioning

confidence: 94%

Mechanisms, monitoring, and management of tyrosine kinase inhibitors-associated cardiovascular toxicities

Chaar

Kamta

Ait‐Oudhia

2018

OTT

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“…Позитивное по FIP1L1-PDGFRА миелопролиферативное заболевание с эозинофилией ленный в литературе опыт использования этого препарата при МПЗ с эозинофилией [31,32], с 21.11.2012 г. начали терапию дазатинибом в дозе 140 мг/сут. Выбор препарата определялся также значительно большей активностью дазатиниба в отношении PDGFRA-тирозинкиназы по сравнению как с иматинибом, так и с нилотинибом: по неопубликованным данным A. Reiter, ингибирующая концентрация дазатиниба составляет 2,9 нМ против 72 нM для иматиниба и 75 нM для нилотиниба.…”

Section: терапевтический архив 12 2015unclassified

FIP1L1-PDGFRА-positive myeloproliferative disease with eosinophilia: A rare case with multiple organ dysfunction and a response to tyrosine kinase inhibitor therapy

Nemchenko

et al. 2015

Ter. arkh.

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The described case of FIP1L1-PDGFRА-positive myeloproliferative disease is characterized by an atypical aggressive course to develop severe specific complications as injuries to the brain, heart, lung, and intestine. Pathogenetic therapy with imatinib could stabilize a patient's state, but failed to produce a complete hematological response. Switching from imatinib to dasatinib could produce sustained clinical, hematological, and molecular remissions.

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“…This study indicated that dasatinib effectively inhibits Src kinase activity and downstream signalling pathways in CML progenitors, but does not induce a strong proapoptotic response. 87 Several preclinical and clinical studies (extensively reported elsewhere [88][89][90] ) culminated with the FDA approval (June 28, 2006) of dasatinib (SprycelTM). This drug is specifically indicated to treat adults with CP, AP, or myeloid or lymphoid blast phase (MB or LB) CML with resistance or intolerance to prior therapy, including imatinib mesylate.…”

Section: A Thiazole-carboxamides (Dasatinib)mentioning

confidence: 99%

New insights into small‐molecule inhibitors of Bcr‐Abl

Schenone

Bruno

Radi

et al. 2010

Medicinal Research Reviews

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Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a defined genetic abnormality, the Bcr-Abl fusion gene on the Philadelphia chromosome that expresses the constitutively activated tyrosine kinase (TK) Bcr-Abl. This enzyme leads to the malignant transformation of primitive hematopoietic cells and to the consequent disease. The central role of Bcr-Abl in the pathogenesis of CML culminated in the discovery of imatinib (an ATP-competitive inhibitor), which is currently the frontline therapy for CML. Unfortunately, the initial enthusiasm generated by its high response rate has been dampened by the development of resistance, especially in the advanced phases of CML. To overcome imatinib resistance, several second-generation ATP-competitive inhibitors endowed with increased potency against imatinib-resistant mutants have been developed: the dual Src/Abl inhibitor dasatinib and the Abl inhibitor nilotinib have been recently approved by US-FDA for the treatment of imatinib-resistant CML, and many other compounds are currently in clinical trial. Although second-generation TK inhibitors have shown to be clinically effective against most of the imatinib-resistant mutants, to date poor results have been obtained in the treatment of the Bcr-Abl T315I mutant. In this review we will report the most interesting second-generation Abl and dual Src/Abl inhibitors recently entered in clinical trial, but also the new ATP-competitive and uncompetitive inhibitors published in the last few years, focusing on their chemical structure, mechanism of action, and structure-activity relationship.

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Preclinical and clinical experience with dasatinib in philadelphia chromosome-negative leukemias and myeloid disorders

Cited by 7 publications

References 79 publications

Mechanisms, monitoring, and management of tyrosine kinase inhibitors-associated cardiovascular toxicities

Mechanisms, monitoring, and management of tyrosine kinase inhibitors-associated cardiovascular toxicities

FIP1L1-PDGFRА-positive myeloproliferative disease with eosinophilia: A rare case with multiple organ dysfunction and a response to tyrosine kinase inhibitor therapy

New insights into small‐molecule inhibitors of Bcr‐Abl

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