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imatinib metabolism

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 approved for indefinite treatment of pediatric CML. Potential side effects regarding growth failure and bone metabolism were reported, however, the data is still scattered in pediatric CML. METHODS: 6 chronic-phase CML children with the IM treatment with a median age of 9.87 years (range 5.33-12.67) were enrolled onto study. Growth, bone mineral density (BMD), bone parameters, 25(OH)-vitamin D3 (25-OHD3) and blood tests including parathyroid hormone (PTH), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGF-BP3), 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...
June 27, 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 BCR-ABL1 oncogene does not operate alone to drive disease emergence, maintenance and progression...
June 14, 2016: Current Drug Targets
Sunita Chhikara, Sudha Sazawal, Pravas Mishra, Rekha Chaubey, Manoranjan Mahapatra, Renu Saxena
Patients with chronic myeloid leukaemia show an excellent response to treatment with imatinib. However, in some patients, the disease is resistant to imatinib. This resistance may be related to the presence of genetic variations on the drug's pharmacokinetics and metabolism. We therefore studied three polymorphisms (C1236T, G2677T and C3435T) in the human multidrug-resistance gene (MDR1) in 86 patients with chronic myeloid leukaemia treated with imatinib. Imatinib resistance was more frequent in patients with TT genotype at locus 1236 than in those with CT/CC genotypes (p=0...
November 2015: National Medical Journal of India
Julia Steiger, Alexander Stephan, Megan S Inkeles, Susan Realegeno, Heiko Bruns, Philipp Kröll, Juliana de Castro Kroner, Andrea Sommer, Marina Batinica, Lena Pitzler, Rainer Kalscheuer, Pia Hartmann, Georg Plum, Steffen Stenger, Matteo Pellegrini, Bent Brachvogel, Robert L Modlin, Mario Fabri
Glucocorticoids are extensively used to treat inflammatory diseases; however, their chronic intake increases the risk for mycobacterial infections. Meanwhile, the effects of glucocorticoids on innate host responses are incompletely understood. In this study, we investigated the direct effects of glucocorticoids on antimycobacterial host defense in primary human macrophages. We found that glucocorticoids triggered the expression of cathelicidin, an antimicrobial critical for antimycobacterial responses, independent of the intracellular vitamin D metabolism...
July 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Ines Hartel, Michael Ronellenfitsch, Christina Wanka, Stefan Wolking, Joachim P Steinbach, Johannes Rieger
The epidermal growth factor (EGFR) pathway is frequently activated in glioblastoma but the clinical efficacy of EGFR inhibitors in malignant glioma has been disappointing. The reasons for the failure of the mechanisms of resistance of these inhibitors are unclear, but may involve factors of the tumor microenvironment such as limited glucose availability and hypoxia. It was therefore examined whether glucose and oxygen influenced the response of glioma cells to EGFR inhibition. Decreased levels of glucose and oxygen led to resistance against the EGFR inhibitor PD153035, whereas high glucose amounts and normoxia sensitised glioma cells towards the inhibitor...
July 2016: International Journal of Oncology
Mark T Duncan, Teresa A DeLuca, Hsin-Yu Kuo, Minchang Yi, Milan Mrksich, William M Miller
Inhibition of histone deacetylases (HDACi) has emerged as a promising approach in the treatment of many types of cancer, including leukemias. Among the HDACs, Class III HDACs, also known as sirtuins (SIRTs), are unique in that their function is directly related to the cell's metabolic state through their dependency on the co-factor NAD(+). In this study, we examined the relation between SIRTs and the growth, survival, and differentiation of K562 erythroleukemia cells. Using a mass spectrometry approach we previously developed, we show that SIRT expression and deacetylase activity in these cells changes greatly with differentiation state (undifferentiated vs...
May 15, 2016: Experimental Cell Research
Amos C Hung, Steven Lo, Ming-Feng Hou, Yi-Chen Lee, Chun-Hao Tsai, Yuan-Yin Chen, Wangta Liu, Yu-Han Su, Yi-Hsuan Lo, Chie-Hong Wang, Shiou-Chen Wu, Ya-Ching Hsieh, Stephen Chu-Sung Hu, Ming-Hong Tai, Yun-Ming Wang, Shyng-Shiou F Yuan
PURPOSE: Visfatin is an adipocytokine involved in cellular metabolism, inflammation, and cancer. This study investigated the roles of extracellular visfatin in breast cancer, and explored underlying mechanisms in clinical and experimental settings. EXPERIMENTAL DESIGN: Associations of serum visfatin with clinicopathologic characteristics and patient survival were assessed with Cox regression models and Kaplan-Meier analyses. Effects of extracellular visfatin on cultured breast cancer cells were examined, followed by in vivo investigation of tumor growth and metastasis in xenograft animal models...
September 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Byung Woong Ko, Jeongsu Han, Jun Young Heo, Yunseon Jang, Soo Jeong Kim, Jungim Kim, Min Joung Lee, Min Jeong Ryu, Ik Chan Song, Young Suk Jo, Gi Ryang Kweon
Long-term imatinib treatment induces drug-resistant chronic myeloid leukemia (CML) cells harboring T315I gate keeper mutation of breakpoint cluster region (BCR)-ABL oncogenic kinase. However, although cell proliferation is coupled with cellular energy status in CML carcinogenesis, the metabolic characteristics of T315I-mutant CML cells have never been investigated. Here, we analyzed cell proliferation activities and metabolic phenotypes, including cell proliferation, oxygen consumption, lactate production, and redox state in the KBM5 (imatinib-sensitive) and KBM5-T315I (imatinib-resistant) CML cell lines...
September 2016: Leukemia & Lymphoma
Sarbari Acharya, Sanjeeb K Sahoo
Chronic myeloid leukemia (CML) has been the hub of exhilarating progress in cancer therapy with the advent of imatinib mesylate. However, therapeutic selectivity and drug resistance are two major issues in imatinib based leukemia therapy prompting development of strategies to surmount imatinib resistance for effective CML therapy. Growing evidences advocate that, cancer cells exhibit augmented intrinsic reactive oxygen species (ROS), due to oncogenic stimulation, amplified metabolic activity, and mitochondrial dysfunction...
April 1, 2016: Journal of Colloid and Interface Science
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