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https://www.readbyqxmd.com/read/29442179/efficacy-and-safety-of-nilotinib-therapy-in-patients-with-newly-diagnosed-chronic-myeloid-leukemia-in-the-chronic-phase
#1
Michihide Tokuhira, Yuta Kimura, Keiji Sugimoto, Tomonori Nakazato, Maho Ishikawa, Isao Fujioka, Tomoiku Takaku, Noriyoshi Iriyama, Eriko Sato, Hiroyuki Fujita, Yoshihiro Hatta, Norio Komatsu, Norio Asou, Masahiro Kizaki, Tatsuya Kawaguchi
ABL1-tyrosine kinase inhibitors (TKIs) have led to dramatic changes in treatment strategies for chronic myeloid leukemia in the chronic phase (CML-CP). However, clinical studies have highlighted increasing numbers of adverse events (AE) with TKIs. Although TKI modification plays a key role in AE management, this process is poorly understood, particularly in terms of the TKI nilotinib. In the present study, we retrospectively analyzed the records of 70 patients with newly diagnosed (ND)-CML-CP who were treated with nilotinib to investigate the drug potency of nilotinib and treatment management...
February 13, 2018: Medical Oncology
https://www.readbyqxmd.com/read/29438985/inhibition-of-ddr1-bcr-signalling-by-nilotinib-as-a-new-therapeutic-strategy-for-metastatic-colorectal-cancer
#2
Maya Jeitany, Cédric Leroy, Priscillia Tosti, Marie Lafitte, Jordy Le Guet, Valérie Simon, Debora Bonenfant, Bruno Robert, Fanny Grillet, Caroline Mollevi, Safia El Messaoudi, Amaëlle Otandault, Lucile Canterel-Thouennon, Muriel Busson, Alain R Thierry, Pierre Martineau, Julie Pannequin, Serge Roche, Audrey Sirvent
The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. Here, we show that nilotinib, a clinically approved drug for chronic myeloid leukaemia, strongly inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS-independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1-mediated BCR phosphorylation on Tyr177, which is important for maintaining β-catenin transcriptional activity necessary for tumour cell invasion...
February 9, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29435021/long-lasting-memory-of-cellular-immunity-in-a-chronic-myeloid-leukemia-patient-maintains-molecular-response-5-after-cessation-of-dasatinib
#3
Tatsuro Jo, Kazuhiro Noguchi, Shizuka Hayashi, Sadaharu Irie, Risa Hayase, Haruna Shioya, Youhei Kaneko, Kensuke Horio, Jun Taguchi
Tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib and nilotinib are primarily used in the initial treatment of chronic phase (CP)-chronic myeloid leukemia (CML), as CMLs harbor the BCR-ABL fusion product. An increased number of lymphocytes and large granular lymphocytes (LGLs) have been observed in patients treated with dasatinib, but not other TKIs. The LGLs have been reported to be primarily natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). In the present study, a CP-CML patient who has maintained molecular response 5 for >2...
March 2018: Oncology Letters
https://www.readbyqxmd.com/read/29434953/molecular-screening-and-the-clinical-impacts-of-bcr-abl-kd-mutations-in-patients-with-imatinib-resistant-chronic-myeloid-leukemia
#4
Betül Koçkan, Tayfur Toptaş, Işik Atagündüz, Ayşe Tülin Tuğlular, Ayşe Özer, Mustafa Akkiprik
The present study aimed to detect the frequency of kinase domain (KD) mutations in order to evaluate their clinical significance and functional importance in 45 patients with chronic myeloid leukemia (CML) who were resistant to imatinib therapy. Sanger sequencing was used (45 patients), along with allele-specific oligonucleotide polymerase chain reaction (ASO-PCR; 3 patients), for the screening of mutations. BCR/ABL KD was amplified by nested PCR and sequencing was performed. Secondly, ASO-PCR was performed to confirm the results of the sequence analysis for E255K mutations...
February 2018: Oncology Letters
https://www.readbyqxmd.com/read/29434033/pdgfrb-mutation-and-tyrosine-kinase-inhibitor-resistance-in-ph-like-acute-lymphoblastic-leukemia
#5
Yingchi Zhang, Yufeng Gao, Hui Zhang, Jingliao Zhang, Fuhong He, Aleš Hnízda, Maoxiang Qian, Xiaoming Liu, Yoshihiro Gocho, Ching-Hon Pui, Tao Cheng, Qianfei Wang, Jun J Yang, Xiaofan Zhu, Xin Liu
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) comprises of approximately 10-15% of childhood ALL cases, many of whom respond exquisitely to tyrosine kinase inhibitors (TKIs), e.g., imatinib in PDGFRB-rearranged ALL. However, some cases developed drug resistance to TKIs with mechanisms poorly understood. In this study, we identified a novel PDGFRB fusion gene, namely AGGF1-PDGFRB, and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation PDGFRBC843G , which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib...
February 6, 2018: Blood
https://www.readbyqxmd.com/read/29431866/monocyte-subsets-and-their-phenotypes-during-treatment-with-bcr-abl1-tyrosine-kinase-inhibitors-for-philadelphia-chromosome-positive-leukemia
#6
Takaaki Konuma, Chisato Kohara, Eri Watanabe, Motoko Mizukami, Etsuko Nagai, Susumu Tanoue, Masamichi Isobe, Koji Jimbo, Seiko Kato, Nobuhiro Ohno, Satoshi Takahashi, Arinobu Tojo
BCR-ABL1 tyrosine kinase inhibitors (TKIs) are effective agents in the treatment of Philadelphia chromosome-positive leukemia. However, vascular events have developed in some patients receiving each TKI. The perturbation of circulating monocyte subsets and their expressions of chemokine and scavenger receptors are associated with the development of cardiovascular events. Here, we examined the subsets of circulating monocytes and their phenotypes in 51 patients treated with imatinib, nilotinib, and dasatinib, and 11 healthy subjects in our institute...
February 12, 2018: Hematological Oncology
https://www.readbyqxmd.com/read/29415932/-management-of-cardiovascular-complications-in-cml-patients-treated-with-tyrosine-kinase-inhibitors
#7
Itaru Matsumura
Tyrosine kinase inhibitors (TKIs) have significantly improved the clinical outcomes of patients with chronic myeloid leukemia (CML). However, patients with CML need to receive TKI therapy for several years. Hence, the safety of long-term TKI treatment warrants utmost attention. Among various adverse events caused by TKI therapy, cardiovascular events (CVEs), such as acute myocardial infarction, cerebral infarction, and pulmonary hypertension, are the most serious with high mortality. TKIs inhibit various off-target molecules involved in the occurrence of CVEs such as c-Kit, platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and Tie-2/Tec...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/29411417/chronic-myeloid-leukemia-2018-update-on-diagnosis-therapy-and-monitoring
#8
Elias Jabbour, Hagop Kantarjian
DISEASE OVERVIEW: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. DIAGNOSIS: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome...
March 2018: American Journal of Hematology
https://www.readbyqxmd.com/read/29404062/a-validated-uplc-ms-ms-method-for-simultaneous-determination-of-imatinib-dasatinib-and-nilotinib-in-human-plasma
#9
Jing Zeng, Hua Lin Cai, Zhi Ping Jiang, Qing Wang, Yan Zhu, Ping Xu, Xie Lan Zhao
A sensitive, rapid, simple and economical ultra-performance liquid chromatography-tandem mass spectrometric method (UPLC-MS/MS) was developed and validated for simultaneous determination of imatinib, dasatinib and nilotinib in human plasma using gliquidone as internal standard (IS). Liquid-liquid extraction method with ethyl acetate was used for sample pre-treatment. The separation was performed on an Xtimate Phenyl column using isocratic mobile phase consisting of A (aqueous phase: 0.15% formic acid and 0...
December 2017: Journal of Pharmaceutical Analysis
https://www.readbyqxmd.com/read/29397828/-correlation-of-serum-concentration-of-nilotinib-with-clinical-efficacy-in-patients-with-chronic-myeloid-leukemia
#10
Tong Wang, Cai-Xia Li, Xiao-Chen Chen, Cai-Hong Gu, Dan Yang, Pu Wang, Qiu Zou, De-Pei Wu
OBJECTIVE: To investigate the correlation of the serum minimal concentrations (Cmins) of nilotinib(NIL) with the clinical efficacy and adverse events (AEs) in CML patients. METHODS: A total of 54 patients were divided into two groups according to the dosage of nilotinib. 44 cases received dose of 600-800 mg/d were classified as group A; while 10 cases received dose of 400 mg/d as group B. The Cmins of nilotinib were determmined by liquid chromatography-tandem mass spectrometry...
February 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29386436/-analysis-of-time-to-onset-of-interstitial-lung-disease-after-the-administration-of-small-molecule-molecularly-targeted-drugs
#11
Fusao Komada
The aim of this study was to investigate the time-to-onset of drug-induced interstitial lung disease (DILD) following the administration of small molecule molecularly-targeted drugs via the use of the spontaneous adverse reaction reporting system of the Japanese Adverse Drug Event Report database. DILD datasets for afatinib, alectinib, bortezomib, crizotinib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, sorafenib, sunitinib, temsirolimus, and tofacitinib were used to calculate the median onset times of DILD and the Weibull distribution parameters, and to perform the hierarchical cluster analysis...
2018: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/29385210/abcc6-plays-a-significant-role-in-the-transport-of-nilotinib-and-dasatinib-and-contributes-to-tki-resistance-in-vitro-in-both-cell-lines-and-primary-patient-mononuclear-cells
#12
Laura N Eadie, Phuong Dang, Jarrad M Goyne, Timothy P Hughes, Deborah L White
ATP Binding Cassette family efflux proteins ABCB1 and ABCG2 have previously been demonstrated to interact with Tyrosine Kinase Inhibitors (TKIs); however, evidence for the interaction of other potentially relevant drug transporters with TKIs is lacking. Through Taqman transporter array technology we assessed the impact of nilotinib on mRNA expression of ABC transporters, with ABCC6 identified as a transporter of interest. Additionally, increased expression of ABCC6 mRNA was observed during in vitro development of nilotinib resistance in BCR-ABL1-expressing cell lines...
2018: PloS One
https://www.readbyqxmd.com/read/29370077/p53-gene-ny-co-13-levels-in-patients-with-chronic-myeloid-leukemia-the-role-of-imatinib-and-nilotinib
#13
Hayder M Al-Kuraishy, Ali I Al-Gareeb, Ali K Al-Buhadilly
The p53 gene is also known as tumor suppressor p53. The main functions of the p53 gene are an anticancer effect and cellular genomic stability via various pathways including activation of DNA repair, induction of apoptosis, and arresting of cell growth at the G1/S phase. Normally, the p53 gene is inactivated by mouse double minute 2 proteins (mdm2), but it is activated in chronic myeloid leukemia (CML). Tyrosine kinase inhibitors are effective chemotherapeutic agents in the management of CML. The purpose of the present study was to evaluate the differential effect of imatinib and nilotinib on p53 gene serum levels in patients with CML...
January 25, 2018: Diseases (Basel)
https://www.readbyqxmd.com/read/29362980/efficacy-and-safety-of-switching-to-nilotinib-in-patients-with-cml-cp-in-major-molecular-response-to-imatinib-results-of-a-multicenter-phase-ii-trial-nilsw-trial
#14
Jun Ishikawa, Itaru Matsumura, Tatsuya Kawaguchi, Junya Kuroda, Hirohisa Nakamae, Toshihiro Miyamoto, Ken-Ichi Matsuoka, Hirohiko Shibayama, Masayuki Hino, Chikara Hirase, Tomohiko Kamimura, Takayuki Shimose, Koichi Akashi, Yuzuru Kanakura
We evaluated the efficacy and safety of switching to nilotinib in CML-CP patients who had achieved MMR with continuous detectable BCR-ABL1 transcript levels after long-term imatinib treatment. Patients who had achieved MMR, but not deep molecular response (DMR), after > 18 months from the initiation of imatinib received nilotinib 400 mg twice daily for up to 24 months. BCR-ABL1 transcript levels were assessed every 3 months. Thirty-eight patients with a median age of 57.5 years (range 22-76 years) were evaluated...
January 23, 2018: International Journal of Hematology
https://www.readbyqxmd.com/read/29355557/blockage-of-endoplasmic-reticulum-stress-attenuates-nilotinib-induced-cardiotoxicity-by-inhibition-of-the-akt-gsk3%C3%AE-nox4-signaling
#15
Qinghui Yang, Liang Wen, Zenghui Meng, Yanjun Chen
Cardiotoxicity is a critical side-effect of nilotinib during treatment for cancer, such as chronic myeloid leukemia, while the potential signaling mechanisms remain unclear. The role of and the relationship between endoplasmic reticulum (ER) stress and mitochondrial dysfunction was investigated in nilotinib-induced cardiac H9C2 injury as a suitable cell model. Our results showed that ER stress was persistently induced in nilotinib-treated cells, evidenced by increase of GRP78, CHOP, ATF4 and XBP1 as well as phospho-PERKThr980...
January 16, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29345355/effects-of-antioxidants-on-apoptosis-induced-by-dasatinib-and-nilotinib-in-k562-cells
#16
Sara Damiano, Serena Montagnaro, Maria Valeria Puzio, Lorella Severino, Ugo Pagnini, Marcella Barbarino, Daniele Cesari, Antonio Giordano, Salvatore Florio, Roberto Ciarcia
In clinical practice for the treatment of chronic myeloid leukemia, second generation of tyrosine kinase inhibitors such as Nilotinib (NIL) specific and potent inhibitor of the BCR/ABL kinase and Dasatinib (DAS) a inhibitor of BCR/ABL and Src family kinase were developed to clinically overcome imatinib resistance. In this study we wanted to test the ability of some antioxidants such Resveratrol (RES) or a new recombinant mitochondrial manganese containing superoxide dismutase (rMnSOD) or δ-tocotrienol (δ-TOCO) to interact with DAS and NIL on viability, reactive oxygen species (ROS) production, lipid peroxidation and apoptosis...
January 18, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29338593/expression-and-role-of-granulocyte-macrophage-colony-stimulating-factor-receptor-gm-csfr-and-granulocyte-colony-stimulating-factor-receptor-g-csfr-on-ph-positive-acute-b-lymphoblastic-leukemia
#17
Yong Wu, Ming Tan, Mei-Ling Chen, Yuan-Zhong Chen
OBJECTIVE: We observed that ph + ALL patients administrated with recombinant human G-CSF (rhG-CSF) after intense chemotherapy have presented a trend of disease relapse. Thus, we aim to thoroughly investigate the expression and role of GM-CSFR and G-CSFR on ph + ALL patients. METHOD: SUP-B15, BALL-1 and primary leukemia cells were used in this study. Transcript levels were analyzed by quantitative PCR while cell viability was measured using a CCK-8 assay...
January 17, 2018: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/29337310/oatp1b2-deficiency-protects-against-paclitaxel-induced-neurotoxicity
#18
Alix F Leblanc, Jason A Sprowl, Paola Alberti, Alessia Chiorazzi, W David Arnold, Alice A Gibson, Kristen W Hong, Marissa S Pioso, Mingqing Chen, Kevin M Huang, Vamsi Chodisetty, Olivia Costa, Tatiana Florea, Peter de Bruijn, Ron H Mathijssen, Raquel E Reinbolt, Maryam B Lustberg, Lara E Sucheston-Campbell, Guido Cavaletti, Alex Sparreboom, Shuiying Hu
Paclitaxel is among the most widely used anticancer drugs and is known to cause a dose-limiting peripheral neurotoxicity, the initiating mechanisms of which remain unknown. Here, we identified the murine solute carrier organic anion-transporting polypeptide B2 (OATP1B2) as a mediator of paclitaxel-induced neurotoxicity. Additionally, using established tests to assess acute and chronic paclitaxel-induced neurotoxicity, we found that genetic or pharmacologic knockout of OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes...
January 16, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29334667/lithium-a-classic-drug-in-psychiatry-improves-nilotinib-mediated-antileukemic-effects
#19
Janaína Peixoto-da-Silva, Andrana K Calgarotto, Katiucha R Rocha, Caroline Palmeira-Dos-Santos, Soraya S Smaili, Gustavo J S Pereira, Fernando V Pericole, Adriana da Silva S Duarte, Sara T O Saad, Claudia Bincoletto
Although Tyrosine kinase inhibitors (TKIs) that target Bcr-Abl play a key role in Chronic Myeloid Leukemia (CML) therapy, they do not eradicate CML-initiating cells, which lead to the emergence of drug resistance. Here we used the lithium, a GSK-3 inhibitor, to attempt to potentiate the effects of nilotinib against leukemia cells. For this purpose, a K562 leukemia cell line and bone marrow cells from untreated Chronic Myeloid Leukemia (CML) patients, prior to any exposure to TKIs, were used as a model. Our results demonstrated that the combination of lithium + nilotinib (L + N) induced K562-cell death and cleaved caspase-3 when compared to lithium or nilotinib alone, accompanied by GSK-3β phosphorylation and Bcr-Abl oncoprotein levels reduction...
January 12, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29327917/peptide-based-photoelectrochemical-cytosensor-using-a-hollow-tio2-eg-znin2s4-co-sensitized-structure-for-ultrasensitive-detection-of-early-apoptotic-cells-and-drug-evaluation
#20
Rong Wu, Gao-Chao Fan, Li-Ping Jiang, Jun-Jie Zhu
The ability to rapidly detect apoptotic cells and accurately evaluate therapeutic effects is significant in cancer research. To address this target, a biocompatible, ultrasensitive photoelectrochemical (PEC) cytosensing platform was developed based on electrochemically reduced graphene (EG)/ZnIn2S4 co-sensitized TiO2 coupled with specific recognition between apoptotic cells and phosphatidylserine (PS)-binding peptide (PSBP). In this strategy, HL-60 cells were selected as a model, and C005, nilotinib and imatinib were selected as apoptosis inducers to show cytosensing performance...
January 12, 2018: ACS Applied Materials & Interfaces
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