TY - JOUR. T1 - Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-α treatment. AU - Hochhaus, Andreas. AU - Druker, Brian. AU - Sawyers, Charles. AU - Guilhot, Francois. AU - Schiffer, Charles A.. AU - Cortes, Jorge. AU - Niederwieser, Dietger W.. AU - Gambacorti, Carlo. AU - Stone, Richard M.. AU - Goldman, John. AU - Fischer, Thomas. AU - OBrien, Stephen G.. AU - Reiffers, Jose J.. AU - Mone, Manisha. AU - Krahnke, Tillmann. AU - Talpaz, Moshe. AU - Kantarjian, Hagop M.. PY - 2008. Y1 - 2008. N2 - Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is the standard of care for chronic myeloid leukemia (CML). A phase 2 trial of imatinib in late chronic-phase (CP) CML after interferon-α (IFNα) failure enrolled 532 patients, 454 with a confirmed diagnosis of CP CML. Median time from diagnosis was 34 months; median duration of imatinib ...
TY - JOUR. T1 - Nilotinib. T2 - A novel Bcr-Abl tyrosine kinase inhibitor for the treatment of leukemias. AU - Jabbour, Elias. AU - El Ahdab, Samih. AU - Cortes, Jorge. AU - Kantarjian, Hagop. PY - 2008/7/1. Y1 - 2008/7/1. N2 - The successful introduction of the tyrosine kinase inhibitors has initiated a new era in the management of chronic myeloid leukemia (CML). Imatinib mesilate therapy has significantly improved the prognosis of CML. A minority of patients in chronic-phase CML - and more patients in advanced phases - are resistant to imatinib, or develop resistance during treatment. This is attributed, in 40 - 50% of cases, to the development of mutations in the Bcr-Abl tyrosine kinase domain that impair imatinib binding. Nilotinib (Tasigna®) is a novel potent selective oral kinase inhibitor. Preclinical and clinical investigations demonstrate nilotinib effectively overcomes imatinib resistance, and has induced high rates of hematologic and cytogenetic responses in CML post imatinib ...
OUTLINE: This is a multicenter, dose-escalation study of imatinib mesylate and cytarabine.. Patients receive oral imatinib mesylate alone once daily on days 1-21. Patients then receive oral imatinib mesylate once daily and cytarabine IV over 1-3 hours on days 1-7. Combination therapy repeats every 28-42 days for 2 courses. Patients then receive maintenance oral imatinib mesylate once daily. Treatment continues in the absence of disease progression or unacceptable toxicity.. Cohorts of 5-20 patients receive escalating doses of imatinib mesylate and cytarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 5/5, 5/10, or 5/20 patients experience dose-limiting toxicity.. Patients are followed every 6 months.. PROJECTED ACCRUAL: A total of 30-60 patients will be accrued for this study within 2 years. ...
A highly mono-selective ortho-methylthiolation of benzamides was achieved via Co-catalyzed coupling of benzamides with DMSO. The reaction employs an 8-aminoquinoline group as the bidentate directing group and DMSO as the methylthiolation source. Instead of a mixture of mono- and di-alkylthio-substituted prod
TY - JOUR. T1 - Recent advances in Philadelphia chromosome-positive malignancies. T2 - the potential role of arsenic trioxide.. AU - ODwyer, Michael E.. AU - La Rosée, Paul. AU - Nimmanapalli, Ramedivi. AU - Bhalla, Kapil N.. AU - Druker, Brian. PY - 2002/4. Y1 - 2002/4. N2 - Chronic myelogenous leukemia (CML) is characterized by the presence of the Bcr-Abl fusion gene, which encodes a constitutively active tyrosine kinase that has been strongly implicated as the sole oncogenic abnormality in early-stage CML. Treatment with the specific tyrosine kinase inhibitor imatinib mesylate has achieved excellent results in CML, at all stages of the disease. However, limitations to the successful use of imatinib mesylate as a single agent include the problem of resistance, seen chiefly in patients with advanced-phase disease. This review summarizes the clinical results to date with imatinib mesylate and briefly discusses the problem of resistance before describing potential strategies, including the use ...
Elevated serum glucocorticoid levels contribute to the progression of many diseases, including depression, Alzheimers disease, hypertension, and acquired immunodeficiency syndrome. Here we show that the benzamide derivative N-[2-(4-cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-1-(tert-butyl-1H-indol-3-yl-methyl)-2-oxo-ethyl]-4-nitrobenzamide (SP-10) inhibits dibutyryl cyclic AMP (dbcAMP)-induced corticosteroid synthesis in a dose-dependent manner in Y-1 adrenal cortical mouse tumor cells, without affecting basal steroid synthesis and reduced stress-induced corticosterone increases in rats without affecting the physiological levels of the steroid in blood. SP-10 did not affect cholesterol transport and metabolism by the mitochondria but was unexpectedly found to increase 3-hydroxy-3-methylglutaryl-coenzyme A, low density lipoprotein receptor, and scavenger receptor class B type I (SR-BI) expression. However, it also markedly reduced dbcAMP-induced NBD-cholesterol uptake, suggesting that this is a
A compound which functions to inhibit capsaicin receptor VR1 activation and is useful as a therapeutic agent for, e.g., various pains including inflammatory pain and neurogenic pain, migraine, cluster headache, and bladder diseases including overactive bladder. It is a benzamide derivative or salt thereof, the derivative being characterized by comprising: a benzene ring; a ring D (a mono- or dicyclic hydrocarbon ring or mono- or dicyclic heteroaromatic ring) bonded to the benzene ring through an amide bond; a ring E (a mono- or dicyclic hydrocarbon ring or mono- or dicyclic heteroaromatic ring) directly bonded to the benzene ring; and A (an amino moiety or a mono- or dicyclic heteroring) bonded to the benzene ring through L (a lower alkylene).
An Open-Label Randomized Phase III Study of Dasatinib vs. High-Dose (600 mg) Imatinib Mesylate in the Treatment of Subjects With Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukemia Who Are Imatinib Failures or Who Have Had a Suboptimal Response After 3-18 Months of Therapy With 400 mg ...
TY - JOUR. T1 - Cardiovascular toxicity in patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors in the real-life practice. T2 - Identification of risk factors and the role of prophylaxis. AU - Caocci, Giovanni. AU - Mulas, Olga. AU - Annunziata, Mario. AU - Luciano, Luigiana. AU - Bonifacio, Massimiliano. AU - Orlandi, Ester Maria. AU - Pregno, Patrizia. AU - Galimberti, Sara. AU - Russo Rossi, Antonella. AU - Abruzzese, Elisabetta. AU - Iurlo, Alessandra. AU - Martino, Bruno. AU - Sgherza, Nicola. AU - Binotto, Gianni. AU - Castagnetti, Fausto. AU - Gozzini, Antonella. AU - Fozza, Claudio. AU - Bocchia, Monica. AU - Sicuranza, Anna. AU - Stagno, Fabio. AU - Efficace, Fabio. AU - Usala, Emilio. AU - De Gregorio, Fiorenza. AU - Scaffidi, Luigi. AU - Elena, Chiara. AU - Pirillo, Francesca. AU - Baratè, Claudia. AU - Trawinska, Malgorzata Monika. AU - Cattaneo, Daniele. AU - Labate, Claudia. AU - Gugliotta, Gabriele. AU - Molica, Matteo. AU - Specchia, ...
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Fingerprint Dive into the research topics of Multicenter Phase II trial assessing effectiveness of imatinib mesylate on relapsed or refractory KIT-positive or PDGFR-positive sarcoma. Together they form a unique fingerprint. ...
The t(9;22) translocation is seen in cases of chronic myeloid leukemia (CML), a subset of acute lymphocytic leukemia (ALL) and rarely in acute myeloid leukemia (AML). The resulting BCR-ABL fusion gene is transcribed and translated into a 210 kD (p210, major transcript) or 190 kD (p190, minor transcript) BCR-ABL fusion product with dysregulated (significantly enhanced) tyrosine kinase activity. Detection of the BCR/ABL1 fusion gene transcript is a critical determinant in diagnosis. The BCR/ABL1 fusion gene product is the cause of disease and growth of leukemic cells and expression levels of the transcript are directly related to disease severity. The use of new drugs for treatment such as the tyrosine kinase inhibitor imatinib mesylate (Gleevec) reduces the amount of leukemic cells below the level of cytogenetic detection and therefore makes molecular determination in the detection of minimal residual disease desirable. A consensus treatment goal is the achievement of major molecular response, ...
In the presence of imatinib mesylate, both age groups displayed little change in spontaneous slow-wave activity with the exception of the highest concentration (Fig. 2ii). A major difference between the two age groups occurred in the amplitude of contractile activity at all concentrations of imatinib mesylate. In the ageing guinea-pig prostate, a concentration-dependent inhibition was seen where low concentrations of imatinib mesylate produced the most inhibition whereas high concentrations produced less inhibition of contractile activity.. In contrast, contractile amplitude was generally reduced to 26-40% across all concentrations in the younger guinea-pig prostate. This difference between age groups may parallel the reduction in pacemaker potential activity and increase in spike potential activity with age, which was previously observed by Dey et al. [14]. Like the guinea-pig bladder [16], the guinea-pig prostate generates nifedipine-sensitive spike potentials, as well as slow-wave activity. ...
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Novel N-(3-hydroxy-4-pipridinyl)benzamides and derivatives thereof, said compounds being used as stimulators of the motility of the gastro-intestinal system.
BACKROUND: The selective tyrosine kinase inhibitor imatinib inhibits growth of bcr/abl positive cells and, thus, has become a novel therapeutic option for the treatment of Ph+ leukaemic patients. Various mutations within the abl sequence have been described that prevent adequate imatinib binding to bcr/abl resulting in cellular resistance of CML cells. METHODS: We investigated 69 CML patients under treatment with imatinib as part of an ongoing clinical trial. At recruitment 37 patients were in chronic phase, 21 patients in accelerated phase and 11 patients in blast crisis. Bcr/abl, WT1, MDR1and AGP RNA transcripts were quantified in peripheral leucocytes by real time PCR. AGP protein levels in plasma were measured by turbidimetric analysis. By combining peptide nucleic acid (PNA) based DNA clamping with a fluorescence hybridisation probe assay we developed a new and highly sensitive technique for the detection of known mutations within the bcr/abl kinase domain. RESULTS: 1. Our results ...
BACKGROUND: The cause of chronic myeloid leukemia (CML) is a constitutively active BCR-ABL tyrosine kinase. Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy. METHODS: We randomly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival; progression to accelerated-phase CML or blast crisis; hematologic, cytogenetic, and molecular responses; and adverse events. RESULTS: The median follow-up was 60 months. Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69% by 12 months and 87% by 60 months. An estimated 7% of patients progressed to accelerated-phase CML or blast crisis, and the estimated overall survival of patients who received imatinib as initial ...
The clinical success of the ABL tyrosine kinase inhibitor imatinib in chronic myeloid leukaemia (CML) serves as a model for molecularly targeted therapy of cancer, but at least two critical questions remain. Can imatinib eradicate leukaemic stem cells? What are the dynamics of relapse due to imatinib resistance, which is caused by mutations in the ABL kinase domain? The precise understanding of how imatinib exerts its therapeutic effect in CML and the ability to measure disease burden by quantitative polymerase chain reaction provide an opportunity to develop a mathematical approach. We find that a four-compartment model, based on the known biology of haematopoietic differentiation, can explain the kinetics of the molecular response to imatinib in a 169-patient data set. Successful therapy leads to a biphasic exponential decline of leukaemic cells. The first slope of 0.05 per day represents the turnover rate of differentiated leukaemic cells, while the second slope of 0.008 per day represents ...
Celecoxib is a selective COX-2 inhibitor and its anti-tumor effect has been reported in various cancers [7-9]. In this paper, we demonstrated that the anti-tumor activities of celecoxib included cell cycle arrest, necrosis, apoptosis and autophagy suppression in KBM5 and KBM5-T315I cells. KBM5-T315I cell is a mutation line of KBM5 with a threonine to isoleucine mutation at position 315 in the Abl fragment of the Bcr-Abl kinase domain. This leads to an alteration of the enzymes active site and makes these cells resistant to the first and second generation of TKI [35]. Results showed that celecoxib caused cytotoxic effect in the two CML cell lines which was dose and time-dependent. When extending the celecoxib incubation time, the inhibition effect was stronger in KBM5-T315I cells than in KBM5 cells (Fig. 1), indicating that celecoxib might be used as a new therapeutic agents in imatinib-resistant CML. In accordance with other reports [19, 21], our findings also confirmed that the anti-tumor ...
Imatinib (STI571 or Gleevec) is a small-molecule inhibitor of the BCR-ABL tyrosine kinase that produces clinical remissions in chronic myeloid leukemia (CML) patients with minimal toxicity (1, 2). Imatinib is now frontline therapy for CML, but resistance is increasingly encountered. Clinical resistance is primarily mediated by mutations within the kinase domain of BCR-ABL and, to a lesser extent, by amplification of the BCR-ABL genomic locus (3). Crystallographic studies revealed that imatinib binds to the adenosine triphosphate (ATP)-binding site of ABL only when the activation loop of the kinase is closed and thus stabilizes the protein in this inactive conformation (4). In addition, the normally smooth contour of the phosphate-binding loop of ABL is distorted by imatinib binding, adding further to the unique conformational requirements for optimal kinase inhibition. These conformation-specific binding requirements contribute to imatinibs selectivity, particularly with regard to the closely ...
Abstract. Imatinib has become the treatment of choice for most with CML. The standard dose (SD) for CP CML is 400 mg daily, but pre-clinical and clinical observ
BACKGROUND AND OBJECTIVES: Imatinib mesylate inhibits ABL tyrosine kinase. This protein serves a complex role in cell cycling and is important in lymphopoiesis. We describe the immunologic findings in patients with chronic myeloid leukemia resistant to or intolerant of interferon (IFN) a who were treated with imatinib. This aspect could be of interest since patients with these characteristics may be exposed to this treatment for long periods. DESIGN AND METHODS: Immunologic and hematologic evaluation (including immunoglobulin levels and parameters of autoimmunity), immunophenotyping analysis of peripheral blood and bone marrow, and cytogenetic bone marrow analysis were performed at sequential time points of the treatment (0, 3, 6, and 9 and 12 months). The relationships among immunologic variables, and between the immunologic findings and response, were investigated. RESULTS: Hypogammaglobulinemia IgG, IgA and IgM developed in 28%, 14% and 22% of the patients, respectively. Lymphocyte counts ...
Study 200 (NCT00261846), a single-arm, open-label, multicenter study in patients with CML who were resistant or intolerant to prior therapy was conducted to evaluate the efficacy and safety of BOSULIF 500 mg once daily in patients with imatinib-resistant or -intolerant CML with separate cohorts for CP, AP, and BP disease previously treated with 1 prior TKI (imatinib) or more than 1 TKI (imatinib followed by dasatinib and/or nilotinib). The definition of imatinib resistance included (1) failure to achieve or maintain any hematologic improvement within 4 weeks; (2) failure to achieve a CHR by 3 months, cytogenetic response by 6 months or major cytogenetic response (MCyR) by 12 months; (3) progression of disease after a previous cytogenetic or hematologic response; or (4) presence of a genetic mutation in the BCR-ABL gene associated with imatinib resistance. Imatinib intolerance was defined as inability to tolerate imatinib due to toxicity, or progression on imatinib and inability to receive a ...
Imatinib mesylate is a specific tyrosine kinase inhibitor that may block the platelet-derived growth factor and transforming growth factor pathways. These pathways are known to provoke fibroblast activation. We evaluated whether imatinib, by inhibiting these pathways, prevents diastolic dysfunction and attenuates myocardial remodeling using spontaneously hypertensive rats (SHRs). Eight-week-old male SHRs were randomly assigned to either imatinib treatment group (30 mg/kg per day; n=10; SHR-I) or hypertensive control group (distilled water, n=10; SHR-C). Wistar-Kyoto rats were used as normal controls (n=10). At 16 weeks, all rats underwent hemodynamic studies and Doppler echocardiography and then were euthanized. Their hearts were extracted for histopathologic, immunoblotting, and quantitative reverse transcriptase polymerase chain reaction analyses. Although imatinib did not affect blood pressure, it markedly reduced perivascular and interstitial fibrosis in the hearts of SHR. Echocardiogram ...
An Open Label, Multi-center Imatinib Roll-over Protocol for Patients Who Have Completed a Previous Novartis-sponsored Imatinib Study and Are Judged by the Investigator to Benefit From Continued Imatinib Treatment
Imatinib has shown remarkable clinical benefit for treatment of Bcr/Abl+ leukemia, especially CML patients in early chronic phase. However, it has become clear that rare clones with mutations that confer resistance to imatinib (e.g., mutations in bcr-abl that prevent imatinib binding) can survive, and this resistance can lead to relapse and limits the effects for patients with advanced disease (1). Because the inhibition of cell proliferation by the blockade of Bcr/Abl with imatinib is not sufficient for eradicating Bcr/Abl+ leukemic clones, a better understanding of the mechanisms by which imatinib kills cells and how this killing can be augmented may lead to improved therapeutic strategies.. Although, our study confirmed that Bcl-2 or Bcl-xL overexpression (7) or RNAi-mediated reduction of Bim (8, 9) inhibits imatinib-induced apoptosis in K562 cells, we found that it is the combination of Bim and Bad that accounts for the killing activity of imatinib. Imatinib caused a marked reduction in ...
TY - JOUR. T1 - Clinical Strategies to Achieve an Early and Successful Response to Tyrosine Kinase Inhibitor Therapy. AU - Hughes, Timothy. AU - Hochhaus, Andreas. PY - 2009/1/1. Y1 - 2009/1/1. N2 - Imatinib is the standard of care for previously untreated chronic myeloid leukemia (CML), with high response rates that lead to improved event-free and overall survival compared with interferon alfa. Imatinib dose is one important factor affecting response, and early clinical studies showed promising molecular response rates with high-dose therapy. Large, randomized trials are now ongoing to test this potential benefit and establish whether a starting dose of 800 mg/d improves long-term clinical outcomes compared with the current standard dose of 400 mg/d. Low plasma imatinib levels are associated with a decreased chance of response. The importance of imatinib dosing and plasma levels is likely due to their impact on intracellular concentrations of the drug. Cellular influx of imatinib is mediated by ...
1. Stoler D.L. , Chen N. , Basik M. et al. The onset and extent of genomic instability in sporadic colorectal tumor progression . Proc Natl Acad Sci U S A . 1999 ; 96 : 15121 - 15126 . 2. Hahn W.C. , Weinberg R.A. Modelling the molecular circuitry of cancer . Nat Rev Cancer . 2002 ; 2 : 331 - 341 . 3. La Rosee P. , ODwyer M.E. , Druker B.J. Insights from pre-clinical studies for new combination treatment regimens with the Bcr-Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: a translational perspective . Leukemia . 2002 ; 16 : 1213 - 1219 . 4. Kitano H. Cancer robustness: tumour tactics . Nature . 2003 ; 426 : 125 . 5. Hetz C. , Soto C. Protein misfolding and disease: the case of prion disorders . Cell Mol Life Sci . 2003 ; 60 : 133 - 143 . 6. Nardai G. , Vegh E.M. , Prohaszka Z. , Csermely P. Chaperone-related immune dysfunction: an emergent property of distorted chaperone networks . Trends Immunol . 2006 ; 27 : 74 - 79 . 7. Zhao R. , Davey M. , Hsu Y.C. ...
OBJECTIVE: Despite the efficacy of the BCR-ABL tyrosine kinase inhibitor imatinib, the development of resistance against imatinib has been observed. The most important mechanisms known to cause resistance are point mutations in the ABL tyrosine kinase and the ATP domain. This study describes the use of denaturing high performance liquid chromatography (dHPLC) as a method to screen for mutations of the ABL gene.METHODS: We used the dHPLC based assay for the screening of ABL point mutations. Forty chronic myeloid leukemia (CML) patients who showed resistance to imatinib were screened in parallel by dHPLC and direct sequencing.RESULTS: Nine of the 40 patients (23%) had mutations. CONCLUSION: dHPLC can be a useful method for pre-screening. Analyzing the mutations and monitoring (high-risk) patients can improve their prognosis and survival rate. dHPLC can potentially become a valuable tool for regular testing of patients in the future ...
C07D213/60-Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms ...
Glivec leukaemia drug binding to its target, the enzyme Bcr-Abl tyrosine kinase. This enzyme is produced by a genetic mutation, the swapping of parts of two chromosomes, leading to the formation of the oncogene (cancer-causing gene) Bcr-Abl, which produces a constantly-active version of normal Abl tyrosine kinase. This causes chronic myelogenous leukaemia (CML), a cancer of white blood cells. The drug Glivec (Imatinib) works by binding to the active site of the Bcr-Abl enzyme, producing a change in shape that prevents the enzyme from functioning. This causes the death of cancerous cells expressing the enzyme. Glivec, the first such tyrosine kinase inhibitor to be produced, is marketed by Novartis. - Stock Video Clip K003/2147
This extension II study will allow for further follow-up of the disease under treatment with imatinib mesylate and allow the patients to continue to receive imatinib mesylate.
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RAD51 is a key protein in the homologous recombination (HR) pathway of DNA double-strand break repair, and HR represents a novel target for cancer therapy. Because imatinib (Gleevec) has been reported to reduce RAD51 protein levels, we tested the clonogenic survival for RT112, H1299, PANC1, and PC3 tumor cell lines of varying p53 status and normal GM05757 normal fibroblasts after exposure to single agent imatinib (0-20 micromol/L; 0-72 hours). We also combined imatinib with DNA damaging agents that are toxic to RAD51-deficient cells, including ionizing radiation, gemcitabine, and mitomycin C. We observed decreased nuclear expression and chromatin binding of RAD51 protein following imatinib treatment. Imatinib also resulted in decreased error-free HR as determined by a flow cytometry-based integrated direct repeat-green fusion protein reporter system; this correlated to reduced RAD51 expression. Clonogenic survival experiments revealed increased cell kill for imatinib-treated cells in combination with
RAD51 is a key protein in the homologous recombination (HR) pathway of DNA double-strand break repair, and HR represents a novel target for cancer therapy. Because imatinib (Gleevec) has been reported to reduce RAD51 protein levels, we tested the clonogenic survival for RT112, H1299, PANC1, and PC3 tumor cell lines of varying p53 status and normal GM05757 normal fibroblasts after exposure to single agent imatinib (0-20 micromol/L; 0-72 hours). We also combined imatinib with DNA damaging agents that are toxic to RAD51-deficient cells, including ionizing radiation, gemcitabine, and mitomycin C. We observed decreased nuclear expression and chromatin binding of RAD51 protein following imatinib treatment. Imatinib also resulted in decreased error-free HR as determined by a flow cytometry-based integrated direct repeat-green fusion protein reporter system; this correlated to reduced RAD51 expression. Clonogenic survival experiments revealed increased cell kill for imatinib-treated cells in combination with
It has been clearly established that response is the most important prognostic factor for long-term outcome in CML.17⇓-19 The depth and time of response obtained by patients with CML during TKI therapy are critical from a prognostic standpoint.17⇓-19 Patients who achieved a CCyR at 12, 18, or 24 months in the IRIS study had improved progression-free survival compared with those who obtained only a partial cytogenetic response at each of those time points.3 Moreover, patients who do not achieve optimal response at 12 months of imatinib therapy had a higher risk of progression and poorer outcome compared with patients who achieved a 12-month CCyR, thus making the 12-month CCyR, the most relevant endpoint.17⇓-19. Our study of homogeneous patients with early CML-CP treated with TKI has confirmed that second-generation TKI used in the frontline setting is highly efficacious and induced higher rates of CCyR early. In addition, our study has confirmed that an early achievement of CCyR remains a ...
Breast cancer accounts for 29% of malignant tumors. It is an heterogenous disease covering a spectrum of different molecular subtypes. Epigenetic aberrations may affect gene expression through DNA and histone proteins modifications thus promoting tumor progression and resistance to anti- tumor treatment. Area covered: This article explores the potential role of entinostat in the treatment of breast cancer. The clinical trials evaluating entinostat are discussed, highlighting preclinical data and early-phase clinical studies results. The emerging activity of entinostat in several clinical settings is evaluated by focusing on endocrine-resistant, HER2 positive and triple-negative breast cancer with promising activity in boosting the immune-system. Expert opinion: Entinostat, a synthetic benzamide derivative class I histone deacetylases (HDACs) inhibitor, inhibits cell proliferation and promotes apoptosis in breast cancer. Several results from clinical trials demonstrate that the addition of an ...
Discussion. The concept of achieving deeper molecular responses with first generation TKIs for a sufficient period of time has been the basis for considering TKI withdrawal, looking for a possible cure in CML. This was defined as a 4-log reduction of BCR-ABL1 transcripts [molecular response (MR)4.0] for more than two years in the Stop Imatinib (STIM) trial as the criteria for imatinib withdrawal. However, the results have shown that 60% of patients had molecular relapse necessitating the reintroduction of TKIs. Hence, deep molecular response does not equate with a cure.7. This same concept was tried in a different setting in a few cases where there was initial imatinib failure due to TKD mutations but deep molecular responses were obtained with the 2nd generation TKI dasatinib. Dasatinib cessation was tried in these cases as well, with no relapse. The presence of BCR-ABL positive cells in the blood of a patient in a stable drug-free CMR appears to indicate that eradication of the leukemic clone ...
Gleevec Gleevec - description, side Effects of Gleevec Gleevec, dosage (Gleevec Gleevec), proper use of Gleevec Gleevec. Drugs review.
Hentschel J, Rubio I, Eberhart M, Hipler C, Schiefner J, Schubert K, Loncarevic IF, Wittig U, Baniahmad A, von Eggeling F. Int J Oncol. 2011 Sep Although the BCR-ABL tyrosine kinase inhibitor Imatinib has undoubtedly revolutionized the therapy of chronic … Continue reading →. ...
Degradation mechanisms of chemicals in sediment must be known in order to permit more accurate assessment of aquatic pollutants. One possible degradation mechanism -- abiotic transformation -- has received little attention, however. In this study, the abiotic transformation of para- substituted benzonitriles in an extract prepared by protein extraction from sediment was compared with that in raw sediment and in water.. In water, the benzonitriles were hydrolyzed to benzoic acid through benzamides at elevated temperature. In anaerobic river sediment, the benzonitriles were transformed to the corresponding benzoic acids, except for iodo- and methoxy-derivatives. In the sediment extract, the benzonitriles, including iodo- and methoxy-derivatives, were transformed to benzoic acids. Benzonitrile transformation did not produce benzamides as intermediates in the latter two media. Transformation in sediment and in sediment extract must have been mediated by an enzyme whose activity is similar to that of ...
The present invention of compounds of formula (I) ##STR00001## a stereochemically isomeric form thereof, an N-oxide form thereof or a pharmaceutically acceptable acid addition salt thereof. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for treating conditions which are related to impairment of gastric emptying.
Duncan DR, Chen PY, Patterson JT, Lee YU, Hibino N, Cleary M, Naito Y, Yi T, Gilliland T, Kurobe H, Church SN, Shinoka T, Fahmy TM, Simons M, Breuer CK. TGFßR1 inhibition blocks the formation of stenosis in tissue-engineered vascular grafts. J Am Coll Cardiol. 2015 Feb 10; 65(5):512-4 ...
Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints. Despite many treatment options for gout, there is a substantial need for alternative treatments for patients unresponsive to current therapies. Tyrosine kinase inhibitors have demonstrated therapeutic benefit in experimental models of antibody-dependent arthritis and in rheumatoid arthritis in humans, but to date, the potential effects of such inhibitors on gouty arthritis has not been evaluated. Here we demonstrate that treatment with the tyrosine kinase inhibitor imatinib mesylate (imatinib) can suppress inflammation induced by injection of MSU crystals into subcutaneous air pouches or into the ankle joint of wild type mice. Moreover, imatinib treatment also largely abolished the lower levels of inflammation which developed in IL-1R1-/- or KitW-sh/W-sh mice, indicating that this drug can inhibit IL-1-independent pathways, as well as mast cell-independent pathways, contributing to pathology in this model. ...
TY - JOUR. T1 - Impact of rechallenge with imatinib in patients with advanced gastrointestinal stromal tumor after failure of imatinib and sunitinib. AU - Sawaki, Akira. AU - Kanda, Tatsuo. AU - Komatsu, Yoshito. AU - Nishida, Toshirou. PY - 2014. Y1 - 2014. N2 - Purpose. This retrospective, nonrandomized study investigated the effect of imatinib rechallenge plus best supportive care (BSC) on overall survival after imatinib and sunitinib treatment for patients with locally advanced or metastatic gastrointestinal stromal tumor (GIST). Methods. Twenty-six patients who had previously been exposed to both imatinib and sunitinib were enrolled in this study. The treatment regimen was BSC with or without imatinib, based on the patients choice after discussion with his or her physician. The primary endpoint was overall survival, and secondary endpoints were time to treatment failure, clinical response rate assessed by Choi criteria, and safety. Results. Fourteen patients were treated with imatinib plus ...
TY - JOUR. T1 - Phase II study of motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate. AU - Sawaki, Akira. AU - Yamada, Yasuhide. AU - Komatsu, Yoshito. AU - Kanda, Tatsuo. AU - Doi, Toshihiko. AU - Koseki, Masato. AU - Baba, Hideo. AU - Sun, Yu Nien. AU - Murakami, Koji. AU - Nishida, Toshirou. PY - 2010/4/1. Y1 - 2010/4/1. N2 - Purpose: Motesanib (AMG 706) is a multitargeted anticancer agent with an inhibitory action on the human vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and the cellular stem-cell factor receptor (KIT). The aim of this single-arm phase II clinical study was to assess the efficacy and safety of single-agent motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate. Methods: All patients had experienced progression or relapse while undergoing with imatinib as 400 mg/day or higher. The patients were ...
The added value of 2nd generation tyrosine kinase inhibitors (TKIs) is currently perhaps the most-discussed issue in chronic myeloid leukemia (CML) research and treatment. Therefore, with their recently published article Second-generation tyrosine kinase inhibitors improve the survival of patients with chronic myeloid leukemia in whom imatinib therapy has failed, Ibrahim et al.1 focussed on an important topic. However, in our opinion, the methodological approach used in this paper is not always appropriate.. The choice of the historical control group treated with interferon-alfa seems not to be optimal. Even before the imatinib era, progress had been made in the treatment of CML as the results of the consecutive German studies and of the French CML-study group show.2-4 We doubt that the results of the 20-year old MRC trial represent an appropriate comparator group for the results achieved by the use of 2nd generation tyrosine kinase inhibitors. Furthermore, the authors use two different ...
Imatinib mesylate (Gleevec, STI571) is a kinase inhibitor selective for Bcr-Abl, activated c-Kit kinases, and platelet-derived growth factor receptor tyrosine kinase. Imatinib mesylate, similar to many other tyrosine kinase inhibitors (TKIs), such as members of the 4-anilinoquinazoline class, competes for ATP binding. Previously, 4-anilinoquinazoline TKIs have been shown to inhibit the function of the breast cancer resistance-associated drug transporter (ABCG2), reversing resistance to camptothecin derivatives topotecan and SN-38. However, the potential to inhibit ABCG2 for the 2-phenylamino-pyrimidine class of TKIs, exemplified by imatinib mesylate, has not been examined. Here, we show that imatinib mesylate potently reverses ABCG2-mediated resistance to topotecan and SN-38 and significantly increases accumulation of topotecan only in cells expressing functional ABCG2. However, overexpression of ABCG2 does not confer resistance to imatinib mesylate. Furthermore, accumulation and efflux of ...
This trial will investigate the efficacy and tolerability of palbociclib in patients with advanced gastrointestinal stromal tumours refractory to imatinib and
Imatinib is a small molecule kinase inhibitor used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec (USA) or Glivec (Europe/Australia) as its mesylate salt, imatinib mesilate (INN). It is occasionally referred to as CGP57148B or STI571 (especially in older publications). It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. It is the first member of a new class of agents that act by inhibiting particular tyrosine kinase enzymes, instead of non-specifically inhibiting rapidly dividing cells ...
TY - JOUR. T1 - Chronic myeloid leukemia following therapy with imatinib mesylate (Gleevec). T2 - Bone marrow histopathology and correlation with genetic status. AU - Frater, John L.. AU - Tallman, Martin S.. AU - Variakojis, Daina. AU - Druker, Brian J.. AU - Resta, Debra. AU - Riley, Mary Beth. AU - Hrisinko, Mary Ann. AU - Peterson, Lo Ann C.. N1 - Copyright: Copyright 2018 Elsevier B.V., All rights reserved.. PY - 2003/6/1. Y1 - 2003/6/1. N2 - We evaluated bone marrow pathologic features and cytogenetic and molecular genetic status of 13 patients with interferon- resistant, chronic-phase chronic myeloid leukemia (CML), treated with imatinib mesylate (Gleevec). All had morphologic evidence of CML in the blood and bone marrow and were positive for bcr-abl by reverse transcriptase-polymerase chain reaction, fluorescence in situ hybridization (FISH), or both. Follow-up marrow biopsies, interphase FISH for bcr-abl, and conventional cytogenetics were performed at 3-month intervals (up to 24 ...
TY - JOUR. T1 - Tyrosine kinase inhibitor therapy can cure chronic myeloid leukemia without hitting leukemic stem cells. AU - Lenaerts, Tom. AU - Pacheco, Jorge M.. AU - Traulsen, Arne. AU - Dingli, David M. PY - 2010/6. Y1 - 2010/6. N2 - Background: Tyrosine kinase inhibitors, such as imatinib, are not considered curative for chronic myeloid leukemia - regardless of the significant reduction of disease burden during treatment - since they do not affect the leukemic stem cells. However, the stochastic nature of hematopoiesis and recent clinical observations suggest that this view must be revisited. Design and Methods: We studied the natural history of a large cohort of virtual patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy using a computational model of hematopoiesis and chronic myeloid leukemia that takes into account stochastic dynamics within the hematopoietic stem and early progenitor cell pool. Results: We found that in the overwhelming majority of patients ...
Targeted molecular agents are a landmark achievement in cancer treatment. In particular, the tyrosine kinase inhibitor imatinib mesylate targets mutant KIT prot...
The significance of molecular response depth is not well defined in patients with chronic phase chronic myeloid leukemia (CP-CML) under imatinib treatment. We retrospectively evaluated clinical records of 178 patients with CP-CML. Eighty-eight patients achieved complete molecular response during long term follow-up. Our results implicate that deeper molecular response is associated with improvement in disease outcome and a slight prolongation in progression-free survival. ...
Read about the report that tyrosine kinase inhibitors therapy is relatively safe for kidney function in chronic myeloid leukemia patients.
After 10 months of imatinib therapy, the patient was referred to our department owing to elevated aminotransferase level without any specific symptoms for several months. He denied any causal alcohol consumption or medication. His physical examination was normal. The laboratory tests revealed the following values: white blood cell count, 4,770/µL; eosinophil count, 467/µL (range, ,500/µL); hemoglobin, 13.8 g/µL; platelet count, 184 K/µL; total protein, 6.34 g/dL; albumin, g/dL, total bilirubin (TB), 1.59 mg/dL; direct bilirubin, 0.31 mg/dL; aspartate aminotransferase (AST), 239 IU/L; alanine aminotransferase (ALT), 393 IU/L; alkaline phosphatase, 194 IU/L (range, 30-120 IU/L); gamma glutamyl transferase, 52 IU/L (range, ,50 IU/L); blood urea nitrogen, 12 mg/dL; creatinine, 1 mg/dL; and international normalized ratio, 1.06. Serologic markers for viral hepatitis, including hepatitis A virus, hepatitis B virus, and hepatitis C virus, were negative. There was no evidence of acute viral ...
PURPOSE Imatinib mesylate is a targeted agent that may be used against Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), one of the highest risk pediatric ALL groups. PATIENTS AND METHODS We evaluated whether imatinib (340 mg/m(2)/d) with an intensive chemotherapy regimen improved outcome in children ages 1 to 21 years with Ph+ ALL (N = 92) and compared toxicities to Ph- ALL patients (N = 65) given the same chemotherapy without imatinib. Exposure to imatinib was increased progressively in five patient cohorts that received imatinib from 42 (cohort 1; n = 7) to 280 continuous days (cohort 5; n = 50) before maintenance therapy. Patients with human leukocyte antigen (HLA) -identical sibling donors underwent blood and marrow transplantation (BMT) with imatinib given for 6 months following BMT. RESULTS Continuous imatinib exposure improved outcome in cohort 5 patients with a 3-year event-free survival (EFS) of 80% +/- 11% (95% CI, 64% to 90%), more than twice historical controls
The KIT-inhibitor imatinib mesylate (IM) has greatly improved the treatment of metastatic gastrointestinal stromal tumors (GIST). IM exhibits strong antiproliferative effects but fails to induce sufficient levels of apoptosis resulting in low pathologic complete remission rates and a high rate of secondary progression in the metastatic setting. Upregulation of p53 by MDM2 inhibitors has been shown to induce apoptosis in p53 wildtype tumors. Analyzing a series of 62 mostly untreated, localized and metastatic GIST we detected a low rate (3%) of inactivating p53 mutations, thus providing a rationale for further exploration of p53-directed therapeutic strategies. To this end, we studied nutlin-3, an inhibitor of the p53 antagonist MDM2, and RITA, a putative p53 activator, in GIST cell lines. Nutlin-3 effectively induced p53 at therapeutically relevant levels, which resulted in moderate antiproliferative effects and cell cycle arrest in p53 wildtype GIST cell lines GIST430, GIST48 and GIST48B. P53
TY - JOUR. T1 - A prospective, multicenter, phase 2 study of imatinib mesylate in Korean patients with metastatic or unresectable gastrointestinal stromal tumor. AU - Ryu, Min Hee. AU - Kang, Won Ki. AU - Bang, Yung Jue. AU - Lee, Kyung Hee. AU - Shin, Dong Bok. AU - Ryoo, Baek Yeol. AU - Roh, Jae Kyung. AU - Kang, Jin Hyoung. AU - Lee, Hyoungnam. AU - Kim, Tae Won. AU - Chang, Heung Moon. AU - Park, Joon Oh. AU - Park, Young Suk. AU - Kim, Taeyou. AU - Kim, Min Kyoung. AU - Lee, Woon Kee. AU - Kang, Hye Jin. AU - Kang, Yoon Koo. PY - 2009/4/1. Y1 - 2009/4/1. N2 - Objectives: This prospective, multicenter, phase 2 study evaluated the efficacy and safety of imatinib mesylate and assessed KIT and PDGFRA gene mutation status in Korean patients with gastrointestinal stromal tumors (GISTs). Methods: Forty-seven patients with pathologically proven KIT-positive metastatic or unresectable GISTs were accrued from eight institutions in Korea. Imatinib was administered orally at 400 mg once daily. In case ...
Currently available medicines in the BCR-ABL TKIs class of drugs include Gleevec and Iclusig, as well as Tasigna, Bosulif, and Sprycel.. These BCR-ABL tyrosine kinase inhibitors (TKIs) are used for the treatment of specific types of blood cancers, including Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL), and less commonly, other types of cancers.. In May 2016 Health Canada issued a safety warning, BCR-ABL Tyrosine Kinase Inhibitors [GLEEVEC (imatinib mesylate), TASIGNA (nilotinib), BOSULIF (bosutinib), SPRYCEL (dasatinib), ICLUSIG (ponatinib hydrochloride)] - Risk of Hepatitis B Reactivation, which did not receive much public attention in the US.. From that May 2016 Health Canada document, we get the following detailed safety information about these drugs:. ...
The DREAM complex in antitumor activity of imatinib mesylate in gastrointestinal stromal tumors. Curr Opin Oncol. 2014 Jul; 26(4):415-21 ...
TY - JOUR. T1 - Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. AU - Guo, Jun. AU - Si, Lu. AU - Kong, Yan. AU - Flaherty, Keith T.. AU - Xu, Xiaowei. AU - Zhu, Yanyan. AU - Corless, Christopher L.. AU - Li, Li. AU - Li, Haifu. AU - Sheng, Xinan. AU - Cui, Chuanliang. AU - Chi, Zhihong. AU - Li, Siming. AU - Han, Mei. AU - Mao, Lili. AU - Lin, Xuede. AU - Du, Nan. AU - Zhang, Xiaoshi. AU - Li, Junling. AU - Wang, Baocheng. AU - Qin, Shukui. N1 - Copyright: Copyright 2011 Elsevier B.V., All rights reserved.. PY - 2011/7/20. Y1 - 2011/7/20. N2 - Purpose: Melanomas harbor aberrations in the c-Kit gene. We tested the efficiency of the tyrosine kinase inhibitor imatinib in selected patients with metastatic melanoma harboring c-Kit mutations or amplifications. Patients and Methods: Forty-three patients with metastatic melanoma harboring c-Kit aberrations were enrolled on this phase II trial. Each patient ...
The FDA has approved bosutinib (Bosulif) to treat chronic myelogenous leukemia (CML). The drug is intended for patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive CML who are resistant to or who cannot tolerate other therapies, including imatinib (Gleevec).. The safety and effectiveness of Bosulif was evaluated in a single clinical trial that enrolled 546 adult patients with chronic, accelerated, or blast phase CML. All patients had disease that progressed after treatment with imatinib or imatinib followed by dasatinib (Sprycel) and/or nilotinib (Tasigna), or who could not tolerate the side effects of prior therapy.. Results showed 34% of patients with chronic phase CML who had been previously treated with imatinib achieved a major cytogenetic response after 24 weeks. Of the patients who achieved a major cytogenetic response at any time, 52.8% had their response last at least 18 months. Among patients previously treated with imatinib followed by dasatinib and/or ...
For hematologic toxicity, treatment should be withheld for an absolute neutrophil count , 1,000 × 106/L or platelets , 50,000 × 106/L until levels increase above these thresholds. Treatment can be resumed at the same dose if recovery occurs within 2 weeks and at a dose reduced by 100 mg if recovery takes , 2 weeks. If cytopenia recurs, the dose should be reduced by an additional 100 mg when restarting treatment after recovery.. Concomitant use of bosutinib with strong CYP3A inhibitors (eg, ketoconazole, itraconazole, clarithromycin), moderate CYP3A inhibitors (eg, erythromycin, fluconazole, diltiazem), or strong CYP3A inducers (eg, rifampin, carbamazepine, phenytoin) should be avoided. Short-acting antacids or H2 blockers should be used as an alternative to proton pump inhibitors.. Safety Profile IN THE TOTAL population of the phase III trial, the most common adverse events of any grade in the bosutinib group were diarrhea (70% vs 34% in imatinib group), nausea (35% vs 38%), thrombocytopenia ...
The development of Imatinib Mesylate (IM), the first specific inhibitor of BCR-ABL1, has had a major impact in patients with Chronic Myeloid Leukemia (CML), establishing IM as the standard therapy for CML.. Despite the clinical success obtained with the use of IM, primary resistance to IM and molecular evidence of persistent disease has been observed in 20-25% of IM treated patients. The existence of second generation TK inhibitors, which are effective in patients with IM resistance, makes identification of predictors of resistance to IM an important goal in CML.. In this study, we have identified a group of 19 miRNAs that may predict clinical resistance to IM in patients with newly diagnosed CML.. CITATION Mol Cancer. 2009 Sep 1;8:69. ...
This work presents the synthesis and spectroscopic characterization of novel methoxy and hydroxy derivates of amidino substituted benzimidazoles and benzamides. Novel compounds were prepared by classical reactions of organic chemistry. Hydroxy derivates of amidino substituted benzimidazoles 13-18 were prepared by the condensation reaction from 4-amidino substituted 1,2-phenylenediamine hydrochlorides 8 and 9 with aromatic aldehydes. In the condensation of corresponding methoxy substituted benzoyl-chlorides 19-21 with p-cyanoaniline methoxy substituted N-(4-cyanophenyl)benzamides 26-28 were prepared. Hydroxy substituted benzamide derivates 29-31 were prepared removing methoxy protection groups using reagents BCl3 and BBr3. Amidino substituted benzamide derivates 33-36 were prepared in the acidic Pinner reaction from the corresponding cyano substituted benzamides 29-30. The Pinner reaction was monitored with IR spectroscopy while the structures of all newly prepared compounds were confirmed by ...
Clinical trial for Chronic myeloid leukemia , Nilotinib Treatment-free Remission Study in CML (Chronic Myeloid Leukemia) Patients
The long-term outcome of imatinib treatment for metastatic GIST has emerged from several large trials. Approximately 45% of patients with metastatic GIST have a measurable response after administration of imatinib, whereas ∼30% will have at least stable disease (15). Although the 2-year survival of patients with metastatic GIST treated with imatinib approximates 72%, half of the patients develop disease progression by 2 years (3). Other investigators (1, 2), with follow-up periods between 24 and 40 weeks, have reported similar rates of progression and resistance to imatinib therapy. In only a minority of cases, patients are insensitive to the drug, a so-called primary resistance.. Most of the above studies have defined clinical response based on imaging methods using the Response Evaluation Criteria in Solid Tumors for solid tumor response to therapy. Few studies have correlated the clinical response with the pathologic response of the tumor. Scaife et al. (16) compared the radiologic and ...
Imatinib mesylate is currently the drug of choice to treat chronic myeloid leukemia. However, patient resistance and cytotoxicity make secondary lines of treatment, such as omacetaxine mepesuccinate, a necessity. Given that drug cytotoxicity represents a major problem during treatment, it is essential to understand the biological pathways affected to better predict poor drug response and prioritize a treatment regime. We conducted cell viability and gene expression assays to determine heritability and gene expression changes associated with imatinib and omacetaxine treatment of 55 non-cancerous lymphoblastoid cell lines, derived from 17 pedigrees. In total, 48,803 transcripts derived from Illumina Human WG-6 BeadChips were analyzed for each sample using SOLAR, whilst correcting for kinship structure. Cytotoxicity within cell lines was highly heritable following imatinib treatment (h2 = 0.60-0.73), but not omacetaxine treatment. Cell lines treated with an IC20 dose of imatinib or omacetaxine showed
Currently available medicines in the BCR-ABL TKIs class of drugs include Gleevec and Iclusig, as well as Tasigna, Bosulif, and Sprycel.. These BCR-ABL tyrosine kinase inhibitors (TKIs) are used for the treatment of specific types of blood cancers, including Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL), and less commonly, other types of cancers.. In May 2016 Health Canada issued a safety warning, BCR-ABL Tyrosine Kinase Inhibitors [GLEEVEC (imatinib mesylate), TASIGNA (nilotinib), BOSULIF (bosutinib), SPRYCEL (dasatinib), ICLUSIG (ponatinib hydrochloride)] - Risk of Hepatitis B Reactivation, which did not receive much public attention in the US.. From that May 2016 Health Canada document, we get the following detailed safety information about these drugs:. ...
Background Tyrosine kinase inhibitors have been shown to have marked clinical efficacy in patients with unresectable or metastatic gastrointestinal stromal tumors (GIST). We performed a comparative...
53 NCCN Guidelines for Patients ® : Chronic Myeloid Leukemia, 2018 Acronyms Acronyms ALL acute lymphoblastic leukemia AML acute myeloid leukemia CAM complementary and alternative medicine CBC complete blood count CCyR complete cytogenetic response CBC complete blood count CML chronic myeloid leukemia CMR complete molecular response DLI donor lymphocyte infusion DNA deoxyribonucleic acid EMR early molecular response FDA Food and Drug Administration FISH fluorescence in situ hybridization GVL graft-versus-leukemia HCT hematopoietic cell transplant HLA human leukocyte antigen IS International Scale NCCN National Comprehensive Cancer Network MMR major molecular response MPN myeloproliferative neoplasm QPCR quantitative reverse transcriptase-polymerase chain reaction TKI tyrosine kinase inhibitor ...
Kronik myeloid l semi tedavisinde kullan lan imatinib mesilat ayn zamanda k k h cre fakt r n de inhibe etmektedir. Imatinib mesilat n baz polistemia veral hastalarda otonom eritroid koloni geli imini inhibe etti i ve flebotomi ihtiyac n azaltt da g sterilmi tir. Bu al mada, imatinib mesilat varl nda, polistemia veral hasta ile sa l kl d rt kontrolden elde edilen periferik kan eritroid nc l h creleri zerine yar -kat ortamda ins lin benzeri b y me fakt r -l (IGF-l), k k h cre fakt r (SCF) ve eritropoietin (EPO) ile interl kin-3 (IL-3), gran losit-koloni stimule edici fakt r n (GM-CSF) ve gran losit-koloni stimule edici fakt r n n (G-CSF) etkisi ara t r ld . Sa l kl kontrollerden elde edilen hematopoietik nc h crelerden eritroid koloni geli imi sadece t m sitokinlerin varl nda g zlendi. Bununla birlikte eritroid kolonilerin say s polistemia veral hastalardan elde edilen say lara ula amad . Imatinib mesilat n eritroid koloni geli imi zerindeki inhibe edici etkisi belirgindi. Polistemia veral ...
The long-term analysis, completed in 2005, continues to demonstrate promising results. Eighty-four percent of the 147 GIST study participants on Gleevec showed clinical improvement during the study period, meaning that their disease stabilized or went into remission. Two of those experienced complete remission. However, some subjects developed resistance to the drug and some experienced a relapse of their cancer ...
The so-called Philadelphia (Ph) chromosome is present in more than 90% of chronic myeloid leukemia (CML) cases. It results in juxtaposition of the 5′ part of the BCR gene on chromosome 22 to the 3′ part of the ABL gene on chromosome 9. Since the majority of CML cases are currently treated with Imatinib, variant rearrangements in general have no specific prognostic significance, although the mechanisms involved in resistance to therapy have yet to be investigated. The T315I mutation within the abl-gene is the most frequent one associated with resistance to tyrosine kinase inhibitors. This study evaluated a Ph chromosome positive CML case resistant to imatinib mesylate. A dic(17;18), loss of TP53 gene, co-expression of b2a2 and b3a2 fusions transcript and a T315I mutation were found. We reported here a novel case of a Ph chromosome positive CML with a secondary abnormality [dic(17;18)], resulting to Glivec resistance but good response to nilotinib. The dic(17;18) might be a marker for poor prognosis