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imatinib metabolism

Jing Liu, Zhiyu Chen, Hanmei Chen, Yingyong Hou, Weiqi Lu, Junyi He, Hanxing Tong, Yuhong Zhou, Weimin Cai
Imatinib mesylate (IM) has dramatically improved the outcomes of gastrointestinal stromal tumor (GIST) patients. However, the clinical responses of IM may considerably vary among single individuals. This study aimed to investigate the influences of genetic polymorphisms of drug-metabolizing enzyme (CYP3A4), transporters (ABCB1, ABCG2), and nuclear receptor (Pregnane X Receptor (PXR, encoded by NR1I2)) on IM plasma levels and related adverse reactions in Chinese GIST patients. A total of 68 Chinese GIST patients who have received IM 300-600 mg/day were genotyped for six single nucleotide polymorphisms (SNPs) (CYP3A4 rs2242480; ABCB1 rs1045642; ABCG2 rs2231137; NRI12 rs3814055, rs6785049, rs2276706), and the steady-state IM trough plasma concentrations were measured by a validated HPLC method...
March 13, 2017: International Journal of Molecular Sciences
Natarajan Harivenkatesh, Lalit Kumar, Sameer Bakhshi, Atul Sharma, Madhulika Kabra, Tirumurthy Velpandian, Ajay Gogia, Shivaram S Shastri, Nihar Ranjan Biswas, Yogendra Kumar Gupta
Polymorphisms in genes coding for imatinib transporters and metabolizing enzymes may affect imatinib pharmacokinetics and clinical response. Aim of this study was to assess the influence of polymorphisms in MDR1 and CYP3A5 genes on imatinib trough levels, cytogenetic and molecular response in patients with CML. Newly diagnosed patients with chronic-phase CML started on imatinib therapy were enrolled and followed up prospectively for 24 months. The following single nucleotide polymorphisms were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene...
March 18, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Wenjing Luo, Yu Xin, Xia Zhao, Feng Zhang, Changqing Liu, Hongwei Fan, Tao Xi, Jing Xiong
BACKGROUND AND PURPOSE: Imatinib mesylate (IM) is first-line anti-chronic myeloid leukemia (CML) therapy as a specific inhibitor of BCR-ABL tyrosine kinase. IM in combination with other drugs has been widely applied in CML treatment, thus the influence of IM on drug metabolism enzymes (DMEs) is crucial to be understood in suggesting rational drug administration. Carboxylesterases (CESs) are important enzymes catalyzing hydrolytic biotransformation and play vital roles in the metabolism of numerous clinical drugs...
January 27, 2017: British Journal of Pharmacology
Sree Harsha Tirumani, Akshay D Baheti, Harika Tirumani, Ailbhe O'Neill, Jyothi P Jagannathan
The management of gastrointestinal stromal tumors (GISTs) has evolved significantly in the last two decades due to better understanding of their biologic behavior as well as development of molecular targeted therapies. GISTs with exon 11 mutation respond to imatinib whereas GISTs with exon 9 or succinate dehydrogenase subunit mutations do not. Risk stratification models have enabled stratifying GISTs according to risk of recurrence and choosing patients who may benefit from adjuvant therapy. Assessing response to targeted therapies in GIST using conventional response criteria has several potential pitfalls leading to search for alternate response criteria based on changes in tumor attenuation, volume, metabolic and functional parameters...
January 2017: Korean Journal of Radiology: Official Journal of the Korean Radiological Society
Szymon Janczar, Beata Zalewska-Szewczyk, Wojciech Mlynarski
Electrolyte abnormalities are hallmark metabolic disturbances during the treatment of acute lymphoblastic leukemia (ALL). Hyponatremia is an ominous laboratory sign in the setting of neoplasia. We analyzed the incidence, risk factors, associations, specific interventions and outcomes of severe hyponatremia in a single-center series of children with ALL. The incidence of severe hyponatremia, defined as serum sodium levels below 130 mmol/L on at least 2 of 3 consecutive days, was 11.9%. History of hyponatremia episode is associated with neurologic complications (P=0...
March 2017: Journal of Pediatric Hematology/oncology
Daniel T Barratt, Hannah K Cox, Andrew Menelaou, David T Yeung, Deborah L White, Timothy P Hughes, Andrew A Somogyi
OBJECTIVE: The aims of this study were to determine the effects of the CYP2C8*3 and *4 polymorphisms on imatinib metabolism and plasma imatinib concentrations in chronic myeloid leukaemia (CML) patients. METHODS: We genotyped 210 CML patients from the TIDELII trial receiving imatinib 400-800 mg/day for CYP2C8*3 (rs11572080, rs10509681) and *4 (rs1058930). Steady-state trough total plasma N-desmethyl imatinib (major metabolite):imatinib concentration ratios (metabolic ratios) and trough total plasma imatinib concentrations were compared between genotypes (one-way ANOVA with Tukey post hoc)...
December 19, 2016: Clinical Pharmacokinetics
Massimo Breccia, Eleonora Arboscello, Andrea Bellodi, Gioia Colafigli, Matteo Molica, Micaela Bergamaschi, Fulvio Massaro, Luisa Quattrocchi, Matteo Sarocchi, Paolo Spallarossa, Giuliana Alimena
Nilotinib was approved for chronic myeloid leukemia patients in chronic phase or accelerated phase after resistance to imatinib or as frontline treatment. The drug, as other tyrosine kinase inhibitor has a specific safety profile with possible occurring metabolic side effects, such as increased glycaemia and cholesterol level, that may result, in predisposed patients, in an increased rate of cardiac and vascular disorders. The objectives of this paper were to focus on the optimal procedures to perform at diagnosis in order to identify patients at risk of possible events and the correct monitoring procedures in order to prevent and manage metabolic and cardiovascular adverse events...
November 2016: Critical Reviews in Oncology/hematology
Adriana Borriello, Ilaria Caldarelli, Debora Bencivenga, Emanuela Stampone, Silverio Perrotta, Adriana Oliva, Fulvio Della Ragione
The hope of selectively targeting cancer cells by therapy and eradicating definitively malignancies is based on the identification of pathways or metabolisms that clearly distinguish "normal" from "transformed" phenotypes. Some tyrosine kinase activities, specifically unregulated and potently activated in malignant cells, might represent important targets of therapy. Consequently, tyrosine kinase inhibitors (TKIs) might be thought as the "vanguard" of molecularly targeted therapy for human neoplasias. Imatinib and the successive generations of inhibitors of Bcr-Abl1 kinase, represent the major successful examples of TKI use in cancer treatment...
October 13, 2016: Oncotarget
Gyöngyi Kirschner, Bernadett Balla, János Kósa, Péter Horváth, Andrea Kövesdi, Gergely Lakatos, István Takács, Zsolt Nagy, Bálint Tóbiás, Kristóf Árvai, Péter Lakatos
Tyrosine kinase inhibitors are widely used for treatment of certain oncohematological diseases. Several clinical studies have confirmed that specific BCR-ABL tyrosine kinase inhibitors alter the physiological process of bone tissue in a complex and unclearly identified manner. Since these treatments are being given to more and more patients, and the therapy takes decades or lasts even lifelong, it is justifiable to obtain more detailed knowledge of the molecular background of these mechanisms. In this article the authors summarize preliminary research results and human clinical observations on imatinib and nilotinib which are related to bone metabolism, and present the results of their own experiments in in vitro osteoblast cultures...
September 2016: Orvosi Hetilap
Worawut Choeyprasert, Thitinun Yansomdet, Rungrote Natesirinilkul, Karn Wejaphikul, Pimlak Charoenkwan
BACKGROUND: Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor and is approved for indefinite treatment of pediatric chronic myelogenous leukemia (CML). Potential side-effects regarding growth failure and bone metabolism have been reported but data are still scarce in pediatric CML. METHODS: Six chronic-phase CML children on IM treatment with a median age of 9.87 years (range, 5.33-12.67 years) were enrolled in the study. Growth, bone mineral density (BMD), bone parameters, 25(OH)-vitamin D3 (25-OHD3) and blood tests including parathyroid hormone, insulin-like growth factor-1 (IGF-1), IGF binding protein 3, thyroid function test and sex hormones were assessed...
August 19, 2016: Pediatrics International: Official Journal of the Japan Pediatric Society
Daniela Hoehn, Jorge E Cortes, L Jeffrey Medeiros, Elias J Jabbour, Juliana E Hidalgo, Rashmi Kanagal-Shamanna, Carlos E Bueso-Ramos
BACKGROUND: We assessed patients with chronic myelogenous leukemia (CML) for serum calcium (Ca), phosphate (PO4), bone alkaline phosphatase, N-telopeptide (NTx), osteoprotegerin (OPG) levels, and trabecular bone area (TBA) in bone marrow (BM) specimens before and after treatment with dasatinib. We identified a significant increase in percentage of TBA in postdasatinib BM (P = .022). This suggests that dasatinib therapy can increase TBA without significant changes in bone and mineral metabolism...
August 2016: Clinical Lymphoma, Myeloma & Leukemia
M Demiray, H Sahinbas, S Atahan, H Demiray, D Selcuk, I Yildirim, A T Atayoglu
Adenoid cystic carcinoma (ACC) is an aggressive malignant neoplasm of the secretory glands. Conventional chemotherapy has poor effectiveness against metastatic ACC. Thus, a novel effective therapy is needed against metastatic ACC. A majority of ACCs (up to 94%) express c-kit. Imatinib is monoclonal antibody with specific activity against c-kit but has not been found to be effective in treating patients with ACC in which c-kit is overexpressed and activated. The NF-κB and mTOR pathways have been shown that ubiquitously and concurrently activated, indicating that the inhibition of these pathways may represent a novel treatment approach for patients with ACC...
August 2016: Complementary Therapies in Medicine
Radana Karlíková, Jitka Široká, David Friedecký, Edgar Faber, Marcela Hrdá, Kateřina Mičová, Iveta Fikarová, Alžběta Gardlo, Hana Janečková, Ivo Vrobel, Tomáš Adam
The discovery of tyrosine kinase inhibitors (TKIs) brought a major breakthrough in the treatment of patients with chronic myeloid leukemia (CML). Pathogenetic CML events are closely linked with the Bcr-Abl protein with tyrosine kinase activity. TKIs block the ATP-binding site; therefore, the signal pathways leading to malignant transformation are no longer active. However, there is limited information about the impact of TKI treatment on the metabolome of CML patients. Using liquid chromatography mass spectrometric metabolite profiling and multivariate statistical methods, we analyzed plasma and leukocyte samples of patients newly diagnosed with CML, patients treated with hydroxyurea and TKIs (imatinib, dasatinib, nilotinib), and healthy controls...
September 2, 2016: Journal of Proteome Research
Gyöngyi Kirschner, Bernadett Balla, Péter Horváth, Andrea Kövesdi, Gergely Lakatos, István Takács, Zsolt Nagy, Bálint Tóbiás, Kristóf Árvai, János Pál Kósa, Péter Lakatos
Numerous clinical observations have confirmed that breakpoint cluster region-abelson fusion oncoprotein tyrosine kinase inhibitors used in leukemia treatment alter bone physiology in a complex manner. The aim of the present study was to analyze the whole transcriptome of cultured murine osteoblasts and determine the changes following treatment with imatinib and nilotinib using Sequencing by Oligonucleotide Ligation and Detection next generation RNA sequencing. This study also aimed to identify candidate signaling pathways and network regulators by multivariate Ingenuity Pathway Analysis...
September 2016: Molecular Medicine Reports
B A Adeagbo, O O Bolaji, T A Olugbade, M A Durosinmi, R A Bolarinwa, C Masimirembwa
WHAT IS KNOWN AND OBJECTIVE: Imatinib mesylate is the first-line drug for the treatment of Philadelphia/bcr-abl positive chronic myeloid leukaemia (CML). It is known to be metabolized mostly by CYP3A4 and CYP3A5 isoforms while its efflux is mediated by the transporters ABCB1 and ABCG2. Genetic polymorphism of some of these enzymes and transporters have been linked with inter-individual variations in the pharmacokinetics of the drug. This study, therefore, investigated the influence of CYP3A5*3, ABCG2 421C>A and ABCB1 3435 C>T genetic polymorphism on the clinical outcome and steady-state trough plasma concentration (TPC) of imatinib in Nigerians with CML...
October 2016: Journal of Clinical Pharmacy and Therapeutics
Raghava Kashyap, Vamshi Krishna Muddu, Sameera Anantamakula, Satya Sri
Dermatofibrosarcoma protuberans (DFSP) is a rare locally aggressive tumor with distant metastases being unusual. We present a case of metastatic DFSP treated with imatinib showing complete metabolic response to treatment.
July 2016: Indian Journal of Nuclear Medicine: IJNM: the Official Journal of the Society of Nuclear Medicine, India
E Ben-Ami, C M Barysauskas, M von Mehren, M C Heinrich, C L Corless, J E Butrynski, J A Morgan, A J Wagner, E Choy, J T Yap, A D Van den Abbeele, S M Solomon, J A Fletcher, G D Demetri, S George
BACKGROUND: This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST. PATIENTS AND METHODS: The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib...
September 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Chien-Feng Li, I-Chieh Chuang, Ting-Ting Liu, Ko-Chin Chen, Yen-Yang Chen, Fu-Min Fang, Shau-Hsuan Li, Tzu-Ju Chen, Shih-Chen Yu, Jui Lan, Hsuan-Ying Huang
The role of deregulated cellular metabolism, particularly lipid metabolism, in gastrointestinal stromal tumors (GISTs) remains unclear. Through data mining of published transcriptomes, we examined lipid metabolism-regulating drivers differentially upregulated in high-risk cases and identified monoglyceride lipase (MGLL) as the top-ranking candidate involved in GIST progression. MGLL expression status was examined in three GIST cell lines and two independent sets of primary localized GISTs. MGLL mRNA abundance and immunoexpression was determined in 70 cases through the QuantiGene assay and H-scoring on whole sections, respectively...
August 2, 2016: Oncotarget
Shanthi Palanivelu, Sugapriya Dhanasekeran, Haseena Banu Hedayathullah Khan, Sachdanandam Tiruvaiyaru Panchanadham
OBJECTIVE: To evaluate the protective effect of Kalpaamruthaa (KA), a modified Siddha preparation, in BCR-ABL(+) leukemic mouse model. METHODS: BCR-ABL leukemia was induced in 6-10-week-old female BALB/c mice by a single tail vein injection of the 12B1 cell line. Leukemia-induced animals were treated with KA at a dosage of 200 mg/kg body weight dissolved in 0.5 mL of olive oil for 14 days by gastrogavage. Imatinib mesylate was used as the control drug. Glycolytic, gluconeogenic, mitochondrial, tricarboxylic acid cycle and respiratory chain enzymes in the spleen and liver of mouse were compared between the control and experiment groups by biochemical assays...
June 23, 2016: Chinese Journal of Integrative Medicine
Danilo Perrotti, Giovannino Silvestri, Lorenzo Stramucci, Justine Yu, Rossana Trotta
The use of imatinib, second and third generation ABL tyrosine kinase inhibitors (TKI) (i.e. dasatinib, nilotinib, bosutinib and ponatinib) made CML a clinically manageable and, in a small percentage of cases, a cured disease. TKI therapy also turned CML blastic transformation into a rare event; however, disease progression still occurs in those patients who are refractory, not compliant with TKI therapy or develop resistance to multiple TKIs. In the past few years, it became clear that the BCRABL1 oncogene does not operate alone to drive disease emergence, maintenance and progression...
2017: Current Drug Targets
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