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| imatinib |
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| CHEBI:45783 |
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| A benzamide obtained by formal condensation of the carboxy group of 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid with the primary aromatic amino group of 4-methyl-N3-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine. Used (as its mesylate salt) for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumours. |
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This entity has been manually annotated by the ChEBI Team.
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CHEBI:305376, CHEBI:38918, CHEBI:45781
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| ChemicalBook:CB7370890, eMolecules:876446, Selleckchem:Imatinib(STI571), ZINC000019632618 |
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more structures >>
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| Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral targeted therapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple tyrosine kinases such as CSF1R, ABL, c-KIT, FLT3, and PDGFR-β. Specifically, it is used for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) that are Philadelphia chromosome–positive (Ph+), certain types of gastrointestinal stromal tumors (GIST), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), systemic mastocytosis, and myelodysplastic syndrome.
Common side effects include vomiting, diarrhea, muscle pain, headache, and rash. Severe side effects may include fluid retention, gastrointestinal bleeding, bone marrow suppression, liver problems, and heart failure. Use during pregnancy may result in harm to the baby. Imatinib works by stopping the Bcr-Abl tyrosine-kinase. This can slow growth or result in programmed cell death of certain types of cancer cells.
Imatinib was approved for medical use in the United States in 2001. It is on the World Health Organization's List of Essential Medicines. A generic version became available in the UK as of 2017. |
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Read full article at Wikipedia
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InChI=1S/C29H31N7O/c1- 21-5-10-25(18-27(21)34-29-31-13-11-26(33-29)24-4-3-12-30-19-24)32-28(37)23-8-6-22(7-9-23)20-36-16-14-35(2)15-17-36/h3-13,18-19H,14-17,20H2,1-2H3,(H,32,37)(H,31,33,34) |
| KTUFNOKKBVMGRW-UHFFFAOYSA-N |
| CN1CCN(Cc2ccc(cc2)C(=O)Nc2ccc(C)c(Nc3nccc(n3)-c3cccnc3)c2)CC1 |
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Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
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apoptosis inducer
Any substance that induces the process of apoptosis (programmed cell death) in multi-celled organisms.
tyrosine kinase inhibitor
Any protein kinase inhibitor that interferes with the action of tyrosine kinase.
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antineoplastic agent
A substance that inhibits or prevents the proliferation of neoplasms.
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View more via ChEBI Ontology
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4-[(4-methylpiperazin-1-yl)methyl]-N-{4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl}benzamide
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4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE
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PDBeChem
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α-(4-methyl-1-piperazinyl)-3'-((4-(3-pyridyl)-2-pyrimidinyl)amino)-p-toluidide
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ChemIDplus
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STI 571
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ChemIDplus
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152459-95-5
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CAS Registry Number
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ChemIDplus
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7671333
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Beilstein Registry Number
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Beilstein
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7671333
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Reaxys Registry Number
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Reaxys
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Zhang Y, Qiang S, Yu Z, Zhang W, Xu Z, Yang L, Wen A, Hang T (2014)
LC-MS-MS determination of imatinib and N-desmethyl imatinib in human plasma.
Journal of chromatographic science 52, 344-350 [PubMed:23574742]
[show Abstract]
A specific and sensitive liquid chromatography-electrospray ionization-tandem mass spectrometric method was developed for the quantification of imatinib and its primary metabolite N-desmethyl imatinib in human plasma. Protein precipitation with methanol was used for sample preparation. High-performance liquid chromatographic separation was performed on a Thermo BDS Hypersil C18 column (4.6 × 100 mm, 2.4 µm) with methanol-water (55:45, v/v) containing 0.1% formic acid and 0.2% ammonium acetate as the mobile phase, using isocratic elution at a flow rate of 0.7 mL/min. Detection was conducted with positive electrospray ionization multiple reaction monitoring of the ion transitions at m/z 494 → 394 for imatinib, 480 → 394 for N-desmethyl imatinib and 297 → 110 for the internal standard (palonosetron). The assay was validated in the concentration ranges of 8-5,000 ng/mL for imatinib and 3-700 ng/mL for N-desmethyl imatinib. The quantification limits for imatinib and N-desmethyl imatinib were 8 and 3 ng/mL, respectively. The intra-day and inter-day precision values of the assay (expressed as percentage relative standard deviation) were less than 15% at all concentration levels within the tested range, and the accuracy values were between 85 and 115%. The established method was successfully applied to the pharmacokinetic study of imatinib mesylate capsules in 24 healthy Chinese volunteers. | Revheim ME, Kristian A, Malinen E, Bruland ØS, Berner JM, Holm R, Joensuu H, Seierstad T (2013)
Intermittent and continuous imatinib in a human GIST xenograft model carrying KIT exon 17 resistance mutation D816H.
Acta oncologica (Stockholm, Sweden) 52, 776-782 [PubMed:23480638]
[show Abstract]
BackgroundAcquired resistance to imatinib is frequently caused by secondary KIT mutations. We have investigated the effects of imatinib in mice with human gastrointestinal stromal tumour (GIST) xenograft which harbours a primary exon 11 deletion mutation and a secondary imatinib resistance mutation D816H in exon 17. Such mutations are commonly present in imatinib-resistant GIST in humans.Material and methodsThe mice were randomly allocated to receive imatinib either continuously or intermittently. Dynamic (18)F-FDG PET was performed and blood volume fraction (vB), rate transfer constants (k1, k2, k3) and metabolic rate of (18)F-FDG (MRFDG) were computed using a three-compartment model. Tumours were evaluated for the mitotic rate and the expression of HIF-1α , caspase-3 and glucose transporters (GLUTs).ResultsBoth intermittent and continuous imatinib delayed tumour growth significantly compared to controls, significantly in favour of the latter. k1 (representing perfusion, vascular permeability and binding of (18)F-FDG to the GLUTs) was significantly higher in the intermittent group compared to the continuous group, as was tumour GLUT-3 expression. k3 (representing internalisation of (18)F-FDG to the cells) and MR(FDG) were significantly lower.ConclusionImatinib delays GIST xenograft growth despite the presence of the D816H resistance mutation. The schedule of imatinib administration may influence tumour glucose uptake rate and metabolic rate. | Trabelsi S, Gaïes E, Sraïri S, Sahnoun R, Daghfous R, Lakhal M, El Aïdli S, Klouz A (2013)
[Imatinib plasma levels in the management of cutaneous side effects induced by imatinib (Glivec®): 2 case reports].
Annales de biologie clinique 71, 203-206 [PubMed:23587588]
[show Abstract]
Imatinib, an antineoplastic drug used to treat certain cancers, has many side effects such as hematologic, neurologic or cutaneous toxicity. These toxicities seem to be due to a high imatinib plasmatic concentration and are frequently controlled by a discontinuation or a dosage reduction of the drug. We report here in 2 cases of cutaneous side effects induced by imatinib in order to demonstrate the necessity of drug monitoring in such cases. In our cases, imatinib is responsible in the occurrence of these side effects. Monitoring plasma levels of imatinib allowed us to judge if levels were toxic or not and to avoid discontinuation of imatinib in some cases. | Oh B, Kim TY, Min HJ, Kim M, Kang MS, Huh JY, Kim Y, Lee DS (2013)
Synergistic killing effect of imatinib and simvastatin on imatinib-resistant chronic myelogenous leukemia cells.
Anti-cancer drugs 24, 20-31 [PubMed:23075630]
[show Abstract]
The antiproliferative effect of simvastatin on tumor cells has been speculated to be by intracellular signal inhibition through 3-hydroxy-3-methylglutaryl acetyl coenzyme A reductase. We examined the killing effect of simvastatin on imatinib-sensitive and resistant chronic myelogenous leukemia (CML) cells (three kinds of CML cell lines representative of each hematopoietic lineage: K562, KCL22, and LAMA84) and T315I and E255K site-directed mutant cells (Ba/F3). The in-vivo effect of simvastatin was determined in K562-xenografted nude mice. Cotreatment with imatinib and simvastatin in imatinib-resistant CML cells showed a synergistic killing effect in K562-R, KCL22-R, LAMA84-R, and E255K mutant cells, but only an additive effect in the T315I mutant cell, although a single treatment of simvastatin strongly inhibited T315I mutant cells. Mechanisms of killing were an induction of apoptosis and cell cycle arrest, through inhibition of tyrosine phosphorylation, and activated STAT5 and STAT3. Simvastatin suppressed the growth of K562-transplanted tumors, and cotreatment with imatinib was more effective in reducing tumor size. Simvastatin also killed primary CD34 cells from patients with CML more efficiently, compared with CD34 CML cells. Our study shows a synergic effect of imatinib and simvastatin both in imatinib-sensitive and imatinib-resistant cells, but more effective synergism in resistant cells. On the basis of these findings, we suggest that a combination of simvastatin and imatinib may be a potential candidate for the treatment of imatinib-resistant CML. | Haouala A, Widmer N, Guidi M, Montemurro M, Leyvraz S, Buclin T, Eap CB, Decosterd LA, Csajka C (2013)
Prediction of free imatinib concentrations based on total plasma concentrations in patients with gastrointestinal stromal tumours.
British journal of clinical pharmacology 75, 1007-1018 [PubMed:22891806]
[show Abstract]
AimTotal imatinib concentrations are currently measured for the therapeutic drug monitoring of imatinib, whereas only free drug equilibrates with cells for pharmacological action. Due to technical and cost limitations, routine measurement of free concentrations is generally not performed. In this study, free and total imatinib concentrations were measured to establish a model allowing the confident prediction of imatinib free concentrations based on total concentrations and plasma proteins measurements.MethodsOne hundred and fifty total and free plasma concentrations of imatinib were measured in 49 patients with gastrointestinal stromal tumours. A population pharmacokinetic model was built up to characterize mean total and free concentrations with inter-patient and intrapatient variability, while taking into account α1 -acid glycoprotein (AGP) and human serum albumin (HSA) concentrations, in addition to other demographic and environmental covariates.ResultsA one compartment model with first order absorption was used to characterize total and free imatinib concentrations. Only AGP influenced imatinib total clearance. Imatinib free concentrations were best predicted using a non-linear binding model to AGP, with a dissociation constant Kd of 319 ng ml(-1) , assuming a 1:1 molar binding ratio. The addition of HSA in the equation did not improve the prediction of imatinib unbound concentrations.ConclusionAlthough free concentration monitoring is probably more appropriate than total concentrations, it requires an additional ultrafiltration step and sensitive analytical technology, not always available in clinical laboratories. The model proposed might represent a convenient approach to estimate imatinib free concentrations. However, therapeutic ranges for free imatinib concentrations remain to be established before it enters into routine practice. | Gandia P, Arellano C, Lafont T, Huguet F, Malard L, Chatelut E (2013)
Should therapeutic drug monitoring of the unbound fraction of imatinib and its main active metabolite N-desmethyl-imatinib be developed?
Cancer chemotherapy and pharmacology 71, 531-536 [PubMed:23183914]
[show Abstract]
PurposeThe European Society for Medical Oncology recommends therapeutic drug monitoring (TDM) for imatinib, based on total plasma concentrations in cases of sub-optimal response, failure, or adverse events. Imatinib is highly bound to alpha-1 acid glycoprotein (AGP) in the plasma. We determined the unbound plasma fraction of both imatinib and its main active metabolite (N-desmethyl-imatinib) in plasma from 44 patients. The objective was to quantify the inter-individual variability of the protein binding of imatinib in order to discuss the potential benefits and limits of TDM of free plasma concentrations.Patients and methodsThe quantification of unbound fraction of imatinib and N-desmethyl-imatinib was performed using plasma ultrafiltration coupled with LC-MS/MS measurement. 60 pre-dose plasma samples were obtained at steady state within TDM in 44 chronic myeloid leukemia patients.ResultsThe mean unbound fractions of imatinib and N-desmethyl-imatinib were 2.94 and 5.10 %, respectively, with inter-individual variability (CV in %) of 57 % for imatinib and 71 % for the metabolite. For 11 patients, repeated blood sampling gave a mean intra-individual variability of 28 % for imatinib and 34 % for N-desmethyl-imatinib. No correlation was observed between these measured individual imatinib unbound fraction values and those obtained using an equation based on AGP levels previously proposed by Widmer et al. The mean N-desmethyl-imatinib/imatinib ratio was determined for both total (0.69) and unbound (1.10) concentrations, with inter-individual variabilities of 71 and 86 %, respectively.ConclusionThe large inter-individual variability for the unbound fraction of both imatinib and N-desmethyl-imatinib warrants further evaluation of the pharmacokinetic-pharmacodynamic relationship as a potential relevant marker of imatinib therapeutic outcomes. | Patel S (2013)
Long-term efficacy of imatinib for treatment of metastatic GIST.
Cancer chemotherapy and pharmacology 72, 277-286 [PubMed:23503753]
[show Abstract]
PurposeImatinib is an effective and approved treatment for advanced gastrointestinal stromal tumor (GIST). Continuous imatinib treatment is recommended by current guidelines. This review summarizes the long-term efficacy and safety of imatinib for patients with metastatic GIST.MethodsKey clinical studies were reviewed-including B2222, S0033, and BFR14-with particular emphasis on recently reported results of the long-term clinical outcome of imatinib for metastatic GIST.ResultsThe B2222 and S0033 studies recently reported 10-year follow-up results that demonstrate the long-term efficacy of imatinib. Furthermore, results from the BFR14 study demonstrate that imatinib treatment should not be interrupted and that the efficacy of imatinib following reintroduction is inferior compared with the continuous administration group. The S0033 study also supports the importance of dose optimization and dose escalation of imatinib in patients with KIT exon 9 mutations or progressive disease. These studies demonstrate that individual patient characteristics should be evaluated for optimal patient management. Managing adverse events proactively is very important to maintain compliance.ConclusionsThe results from these studies demonstrate that long-term imatinib extends survival in patients with advanced GIST. Furthermore, these studies support the safety of long-term imatinib therapy in this patient population. | Zhang FH, Ling YW, Zhai X, Zhang Y, Huang F, Fan ZP, Zhou HS, Jiang QL, Sun J, Liu QF (2013)
The effect of imatinib therapy on the outcome of allogeneic stem cell transplantation in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia.
Hematology (Amsterdam, Netherlands) 18, 151-157 [PubMed:23394269]
[show Abstract]
ObjectiveTo evaluate the efficacy of imatinib administration before and/or after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).MethodPatients with imatinib therapy time exceeding 30 days pre-/post-transplant were screened in our data. Imatinib was used in induced or consolidated chemotherapy pre-transplant, or maintenance therapy after 60 days post-transplant (therapy time was less than 180 days) regardless of the molecular status of the disease.ResultsSixty-nine patients with Ph+ ALL were enrolled in the retrospective analysis. Forty-four patients received imatinib therapy, including 24 pre-transplant, 9 post-transplant, and 11 both pre- and post-transplant. With a median follow-up time of 395 days (range, 55-2762 days) post-transplant, 3-year estimated overall survival was 62.3 ± 16.6, 40.0 ± 21.9, 41.7 ± 22.2, and 25.9 ± 11.4%, respectively (P = 0.221), and disease-free survival (DFS) was 53.6 ± 17.9, 20.0 ± 17.9, 33.3 ± 25.5% and 23.6 ± 11.4%, respectively (P = 0.421), in patients with imatinib therapy pre-transplant, post-transplant, both pre- and post-transplant, neither pre- nor post-transplant. The incidence of relapse at 3 year for patients with imatinib therapy post-transplant (n = 20) was 63.6%, comparing with 24.2% (P = 0.018) in patients without imatinib therapy post-transplant (n = 49). The ratio of CD4+CD25+Foxp3+ cells in blood was significantly higher at 30 and 60 days after imatinib therapy than that at the time of pre-imatinib in 20 patients (P = 0.019 and 0.001, respectively).ConclusionsApplication of imatinib pre-transplant might have benefited for patients with Ph+ ALL. Whether administration of imatinib, regardless of the molecular status of the disease post-transplant increases relapse, is a worthy goal for further study. | Ito T, Ogawa R, Uezumi A, Ohtani T, Watanabe Y, Tsujikawa K, Miyagoe-Suzuki Y, Takeda S, Yamamoto H, Fukada S (2013)
Imatinib attenuates severe mouse dystrophy and inhibits proliferation and fibrosis-marker expression in muscle mesenchymal progenitors.
Neuromuscular disorders : NMD 23, 349-356 [PubMed:23313020]
[show Abstract]
Imatinib mesylate inhibits signaling of tyrosine kinase receptors, including PDGFRα, and has been used for human cancer therapy. Recent studies have indicated that imatinib is also effective in treatment of some chronic diseases with fibrosis. Fibrosis is the feature of Duchenne muscular dystrophy. It has been reported that imatinib attenuates fibrosis in mdx mice. Recently we revealed that PDGFRα is specifically expressed in muscle mesenchymal progenitors, which are the origin of muscle fibrosis. Here, we show that imatinib ameliorates the muscular pathology of DBA/2-mdx, a more severe mouse muscular dystrophy. In addition, imatinib inhibits both the proliferation and fibrosis marker expression induced by PDGF-AA in muscle mesenchymal progenitors in vitro. Importantly, the effective dose of imatinib on muscle mesenchymal progenitors did not inhibit myoblast proliferation. These results suggest that imatinib targets mesenchymal progenitors, and that a therapeutic strategy targeting mesenchymal progenitors could be a potential treatment for muscular dystrophies. | Li J, Dang YZ, Gao J, Shen L (2013)
[Efficacy observation on imatinib adjuvant therapy with longer duration in patients with gastrointestinal stromal at intermediate or high risk of recurrence].
Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery 16, 216-220 [PubMed:23536338]
[show Abstract]
ObjectiveTo evaluate the recurrence-free survival (RFS) and safety of imatinib adjuvant therapy with longer treatment duration in patients undergoing complete resection of localized primary gastrointestinal stromal tumor (GIST).MethodsClinical and follow-up data of 101 GIST patients between March 2004 and May 2009 with intermediate or high recurrence risk receiving imatinib adjuvant treatment and more than 3 years follow-up time in Peking University Cancer Hospital were retrospectively analyzed. Imatinib adjuvant treatment: 3 patients discontinued less than 1 year imatinib treatment because of adverse events; 24, 21 and 18 patients discontinued imatinib after 1 year, 2 years, and 3 years treatment; 8 patients received 3 years adjuvant treatment and were ongoing; 27 patients received more than 4 years imatinib adjuvant treatment.ResultsThe median follow-up time was 60 months (95%CI:57.9-62.1). Nineteen patients had GIST recurrence, of whom recurrence happened during imatinib adjuvant therapy in 5 patients and after imatinib treatment in 14 patients. The median period from imatinib stopping to recurrence was 12.0 months (95%CI:9.6-14.4). Patients with recurrent GIST achieved tumor control after imatinib resumption. RFS of patients (n=53) with ≥3 years imatinib treatment duration was higher than that of patients (n=48) with <3 years imatinib duration (93.9% vs. 68.0%, P<0.01). In addition, prolonged adjuvant imatinib duration did not significantly increase the adverse events related to treatment (P>0.05).ConclusionsProlonged adjuvant imatinib duration may further improve RFS rate further in patients with intermediate or high risk of recurrence after complete tumor resection without increased adverse events. | Roth O, Spreux-Varoquaux O, Bouchet S, Rousselot P, Castaigne S, Rigaudeau S, Raggueneau V, Therond P, Devillier P, Molimard M, Maneglier B (2010)
Imatinib assay by HPLC with photodiode-array UV detection in plasma from patients with chronic myeloid leukemia: Comparison with LC-MS/MS.
Clinica chimica acta; international journal of clinical chemistry 411, 140-146 [PubMed:19853594]
[show Abstract]
BackgroundImatinib, a competitive inhibitor of BCR-ABL tyrosine kinase, is now the first-line treatment for chronic myelogenous leukemia (CML). Therapeutic drug monitoring targeting trough plasma levels of about 1000ng/mL may help to optimize the therapeutic effect.MethodsWe developed a high-performance liquid chromatography (HPLC) method with UV/Diode Array Detection (DAD) for trough imatinib concentration determination in human plasma. Imatinib trough levels were measured in plasma from 65 CML patients using our method and LC-MS/MS as the reference method. Results with these two methods were compared using Deming regression, chi-square test, and sign test.ResultsThe calibration curve was prepared in blank human plasma. HPLC-UV/DAD calibration curves were linear from 80 to 4000ng/mL, and the limit of quantification was set at 80ng/mL. The between-day variation was 6.1% with greater than 96% recovery after direct plasma deproteinization and greater than 98% recovery from the column. No significant differences in imatinib plasma levels were found between HPLC-UV/DAD and LC-MS/MS.ConclusionsThis HPLC-UV/DAD method was sufficiently specific and sensitive for imatinib TDM, with no evidence of interference. Our rapid inexpensive HPLC-UV/DAD method that requires only widely available equipment performs well for plasma imatinib assays. | Parkkila S, Innocenti A, Kallio H, Hilvo M, Scozzafava A, Supuran CT (2009)
The protein tyrosine kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian alpha-carbonic anhydrase isoforms.
Bioorganic & medicinal chemistry letters 19, 4102-4106 [PubMed:19527930]
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The protein tyrosine kinases (PTKs) are essential enzymes in cellular signaling processes that regulate cell growth, differentiation, migration and metabolism. Their inhibition was recently shown to constitute a new modality for treating cancers. Two clinically used PTK inhibitors (PTKIs), imatinib (Glivec/Gleevec) and nilotinib (Tasigna) were investigated for their effects on the zinc enzymes carbonic anhydrases (CAs, EC 4.2.1.1). The two PTKIs inhibited all 13 catalytically active mammalian isoforms CA I-XV with K(I)s in the range of 4.1nM-20.2microM. CA I and CA II were the most potently inhibited isoforms (K(I)s of 4-32nM), whereas CA VA and VB showed the lowest affinity for these drugs (K(I)s of 5.4-20.2microM). In cancer cells, these inhibitors may interact with CAs in addition to the targets for which they were designed, the PTKs. | Kiesel H, Müller AM, Schmitt-Graeff A, Veelken H (2009)
Dramatic and durable efficacy of imatinib in an advanced angiosarcoma without detectable KIT and PDGFRA mutations.
Cancer biology & therapy 8, 319-321 [PubMed:19182535]
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The tyrosine kinase (TK) inhibitor, imatinib, has revolutionized therapy of malignancies that are addicted to one of its target kinases, c-abl, c-kit and PDGF-R. This addiction is generally dependent on the acquisition of an activating kinase mutation, e.g., the bcr-abl fusion gene in chronic myeloid leukemia, or point mutations of KIT or PDGFRA in gastrointestinal stroma tumors (GIST). Other types of sarcomas are generally considered to be insensitive to imatinib. We have observed a striking and durable remission of an advanced angiosarcoma to imatinib that can only be explained by TK addiction. Unexpectedly, GIST-type KIT and PDGFRA mutations were absent in this case. This case illustrates the diagnostic challenges in identifying individual candidate patients for TK inhibitor therapy. | Weigel MT, Meinhold-Heerlein I, Bauerschlag DO, Schem C, Bauer M, Jonat W, Maass N, Mundhenke C (2009)
Combination of imatinib and vinorelbine enhances cell growth inhibition in breast cancer cells via PDGFR beta signalling.
Cancer letters 273, 70-79 [PubMed:18809244]
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IntroductionImatinib mesylate is a tyrosine kinase receptor inhibitor targeted against PDGFR alpha and beta, c-kit and bcr-abl. These receptors regulate cellular processes such as proliferation, differentiation, and survival. This study was performed to evaluate the effects of imatinib on breast cancer cell lines with respect to the activity of PDGFR beta and Akt: a downstream modulator of cell growth and survival.MethodsExpression of imatinib targets was analyzed with reverse transciptase PCR and immunoblotting assays in the breast cell lines MDA MB 231, MCF 7, ZR 75-1, and T 47-D. Changes on receptor expression and phosphorylation status under imatinib were evaluated using drug concentrations of 2 to 10 microM. The anti-proliferative and pro-apoptotic effects of imatinib alone and in combination with vinorelbine were investigated with an MTT and TUNEL assay.ResultsImatinib inhibited growth and induced apoptosis of all cell lines examined. This effect was increased when combined with vinorelbine. A dose-dependent inhibitory effect on the phosphorylation of PDGFR beta and Akt was detected.ConclusionsThe growth inhibitory effect of imatinib on breast cell lines may be caused by inhibiting the activity of the tyrosine kinases PDGFR beta and Akt. Imatinib is a promising novel drug for targeted therapy of breast cancer patients. | Timmer-de Mik L, Kardaun SH, Kramer MH, Hayes DP, Bousema MT (2009)
Imatinib-induced pseudoporphyria.
Clinical and experimental dermatology 34, 705-707 [PubMed:19077095]
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Imatinib, a synthetic tyrosine kinase inhibitor, is used as first-line therapy for chronic myeloid leukaemia. Imatinib treatment is associated with a variety of adverse effects, most of which are mild to moderate and generally abate after the first months of treatment. Cutaneous adverse reactions are often encountered in patients using imatinib. Pseudoporphyria is regularly associated with the use of medication, especially naproxen and other nonsteroidal anti-inflammatory drugs, but the list of culprits is expanding. We present a patient with imatinib-induced pseudoporphyria. Taking into account the rapidly growing use of imatinib, physicians should be aware of the possibility of imatinib-induced pseudoporphyria. Adequate photoprotection can improve treatment compliance. | Huang X, Patel S, Ahmed N, Seiter K, Liu D (2009)
Severe toxicity of skin rash, fever and diarrhea associated with imatinib: case report and review of skin toxicities associated with tyrosine kinase inhibitors.
Drug design, development and therapy 2, 215-219 [PubMed:19920908]
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Chronic myeloid leukemia (CML) is characterized by a Philadelphia chromosome which contains an oncogene, bcr-abl. This oncogene encodes a tyrosine kinase which is constitutively activated. Imatinib, a tyrosine kinase inhibitor (TKI), has been widely used in the treatment of CML. Dasatinib and nilotinib were recently approved for the treatment of CML. Other TKIs, such as bosutinib, erlotinib, and sunitinib, are under study for the treatment of CML as well as other hematologic and solid malignancies. Skin rash has been reported as one of the most common side effects of the TKIs. Here we present a case of severe skin rash together with unusual symptoms of high fever and diarrhea induced by imatinib in a CML patient. The dermatologic toxicities from a variety of tyrosine kinase inhibitors are reviewed and general principles of management are also discussed. | Wolf D, Rumpold H (2009)
A benefit-risk assessment of imatinib in chronic myeloid leukaemia and gastrointestinal stromal tumours.
Drug safety 32, 1001-1015 [PubMed:19810774]
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Targeting constitutively activated tyrosine kinases, such as BCR-ABL, in chronic myeloid leukaemia (CML) and c-KIT in gastrointestinal stromal tumours (GIST) has substantially changed the clinical management of both diseases. The introduction of imatinib, a tyrosine kinase inhibitor mainly targeting BCR-ABL, c-KIT and PDGFR, has profoundly improved the prognosis of both entities, while being surprisingly well tolerated. This article summarizes recent data on clinical efficacy as well as safety aspects of imatinib for treatment of CML and GIST, including a final benefit-risk assessment. Imatinib induces high rates of cytogenetic and molecular responses in all phases of CML and also has substantial activity in GIST patients. In both diseases, only a few adverse effects, such as musculoskeletal and joint pain, muscle cramps, oedema and gastrointestinal symptoms, occur. Most of these are grade I or II toxicities and generally occur during the early phase of treatment (i.e. within the first 2 years). Thus, in view of the low rates of severe toxicities and the extraordinary efficacy of the drug in both diseases, imatinib represents an oral drug with a high benefit-risk ratio for the treatment of CML and GIST. | Wiwanitkit V (2009)
Analysis of binding energy activity of imatinib and Abl tyrosine kinase domain based on simple consideration for conformational change: An explanation for variation in imatinib effect in mutated type.
Indian journal of cancer 46, 335-336 [PubMed:19749465]
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Imatinib is a clinically well-tolerated small molecule inhibitor that exerts selective, dual inhibition on the transforming growth factor beta and platelet-derived growth factor pathways. The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly motif is flipped by approximately 180 degrees with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat chronic myelogenous leukemia. However, conformational analysis shows that the effect of the drug depends on the potential energy, which varies due to the alpha rotatable angles of the Abl tyrosine kinase domain. In this study, the author determines the change of binding energy between the Abl tyrosine kinase domain, due to the variation in rotatable angles, and bond lengthening. According to this study, the ratio between the required binding energy between the wild and mutated types is equal to 1: 1.16. | Gardner ER, Smith NF, Figg WD, Sparreboom A (2009)
Influence of the dual ABCB1 and ABCG2 inhibitor tariquidar on the disposition of oral imatinib in mice.
Journal of experimental & clinical cancer research : CR 28, 99 [PubMed:19591692]
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BackgroundImatinib, a tyrosine kinase inhibitor currently approved for treatment of several malignancies, has been shown to be a substrate for multiple efflux-transporter proteins, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP). The effect of inhibiting these transporters on tissue exposure to imatinib remains unclear.ObjectiveTo assess the role of these transporters on drug disposition, 50 mg/kg imatinib was administered to Balb/C mice, 30 minutes after receiving tariquidar (10 mg/kg), an inhibitor of both ABCB1 and ABCG2, or vehicle, via oral gavage.MethodsQuantitative determination of imatinib in mouse plasma, liver and brain was performed using a newly-developed and validated liquid-chromatography-mass spectrometric method.ResultsExposure to imatinib was 2.2-fold higher in plasma, liver and brain in mice that received tariquidar, as compared to those that received the vehicle (P = 0.001). The peak plasma concentration did not increase substantially, suggesting that tariquidar is affecting the distribution, metabolism and/or excretion of imatinib, rather than absorption. Though tariquidar increased the absolute exposure of imatinib, the brain-to-plasma ratio of imatinib was unaffected.ConclusionThis study suggests that intentional inhibition of ABCB1 and ABCG2 function at the blood-brain barrier is unlikely to significantly improve clinical outcome of imatinib with currently used dosing regimens. | Iyoda M, Hudkins KL, Becker-Herman S, Wietecha TA, Banas MC, Guo S, Meyer-Bahlburg A, Kowalewska J, Liu G, Ziegler SF, Rawlings DJ, Alpers CE (2009)
Imatinib suppresses cryoglobulinemia and secondary membranoproliferative glomerulonephritis.
Journal of the American Society of Nephrology : JASN 20, 68-77 [PubMed:19020005]
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Imatinib is a receptor tyrosine kinase inhibitor that blocks the activity of c-Abl, c-Kit, and PDGF receptors. We tested the protective effects of imatinib in thymic stromal lymphopoietin transgenic mice, a model of cryoglobulinemia and associated membranoproliferative glomerulonephritis (MPGN), in which some glomerular manifestations likely result from PDGF receptor activation. Surprising, administration of imatinib beginning at weaning suppressed production of cryoglobulin, attenuating both the renal injury and systemic features of cryoglobulinemia. Flow cytometry suggested that inhibition of B cell development in the bone marrow likely caused the reduction in cryoglobulin production. In addition, administration of imatinib to thymic stromal lymphopoietin transgenic mice with established MPGN also diminished cryoglobulin production and reversed the renal and systemic lesions. These data suggest that treatment with imatinib may be a novel therapeutic approach for cryoglobulinemia and MPGN in humans. | Iyoda M, Shibata T, Kawaguchi M, Yamaoka T, Akizawa T (2009)
Preventive and therapeutic effects of imatinib in Wistar-Kyoto rats with anti-glomerular basement membrane glomerulonephritis.
Kidney international 75, 1060-1070 [PubMed:19242505]
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Imatinib is a selective tyrosine kinase inhibitor that can block activity of the platelet-derived growth factor receptor (PDGFR) and that has immunomodulatory effects on various cell types. Here we measured the protective effects of imatinib in Wistar-Kyoto rats with nephrotoxic serum nephritis, a kidney disease model where CD8+ T cells and macrophages play pathogenetic roles. Groups of animals were given imatinib from one day before up to 13 days following induction of nephritis and from day 7 to 20 following disease induction. Compared to control rats, at each time point imatinib treatment caused significantly less proteinuria, lowered serum blood urea nitrogen and creatinine, and decreased the number of glomeruli with necrosis, crescents, and fibrin deposits. Imatinib-treated rats had a significant reduction in glomerular macrophage accumulation and reduced renal cortical PDGFR-beta and M-CSF receptor mRNA expression. Using colocalization we found that glomerular macrophages had reduced IL-1beta and MCP-1 protein expression. Late imatinib treatment significantly reduced proteinuria, serum blood urea nitrogen, and creatinine, and reversed renal histopathological changes. We show that imatinib has renoprotective and therapeutic properties and provide pre-clinical work that will need to be confirmed in patients with crescentic glomerulonephritis. | Biswas SK, Zhao Y, Sandirasegarane L (2009)
Imatinib induces apoptosis by inhibiting PDGF- but not insulin-induced PI 3-kinase/Akt survival signaling in RGC-5 retinal ganglion cells.
Molecular vision 15, 1599-1610 [PubMed:19693287]
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PurposePlatelet-derived growth factor (PDGF) and insulin promote the survival of neuronal cells, including retinal ganglion cells (RGCs), via activation of phosphoinositide 3-kinase (PI 3-kinase)/Akt signaling. Of importance, recent studies have shown that imatinib inhibition of PDGF receptors induces retinal toxicity in some patients. To date, the extent of activation and the functional significance of insulin-induced PI 3-kinase/Akt signaling remain unclear in the context of dysregulated PDGF receptor signaling in retinal cells. In the present study, we tested the hypothesis that the pro-survival effect of insulin-induced PI 3-kinase/Akt signaling is compromised by imatinib inhibition of PDGF receptor signaling in RGCs.MethodsRGC-5 cells were subjected to acute and long-term treatments with imatinib, a PDGF receptor tyrosine kinase inhibitor. Afterwards, the changes in RGC phenotype and apoptotic markers were assessed by fluorescence and phase contrast microscopy and caspase-3/poly(ADP-ribose) polymerase (PARP) cleavage, respectively. In addition, imatinib regulation of PDGF- and insulin-induced PI 3-kinase/Akt survival signaling was determined by immunoblot analyses, immunoprecipitation, and in vitro PI 3-kinase assays.ResultsTreatment of RGC-5 cells with imatinib for up to 48 h resulted in apoptosis, which was not rescued by insulin supplementation. The apoptotic phenotype was associated with upregulation of cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase. Time dependency experiments revealed that imatinib-mediated apoptosis was preceded by early and sustained abrogation of PDGF-induced increases in PDGF receptor tyrosine phosphorylation and phosphotyrosine-associated PI 3-kinase activity. In addition, imatinib inhibited PDGF-induced downstream phosphorylation of Akt, GSK-3beta, and p70S6kinase. However, imatinib exposure did not affect insulin-induced insulin receptor substrate (IRS)-associated PI 3-kinase activity and the downstream phosphorylation of Akt, GSK-3beta, and p70S6kinase.ConclusionsTogether, these data indicate that disruption of PDGF receptor signaling compromises the pro-survival effect of insulin-induced IRS-dependent PI 3-kinase/Akt signaling in RGCs, and that the maintenance of PDGF-induced PI 3-kinase/Akt signaling is critical for the survival of retinal neuronal cells. | Lin AY, Fisher GA, So S, Tang C, Levitt L (2008)
Phase II study of imatinib in unresectable hepatocellular carcinoma.
American journal of clinical oncology 31, 84-88 [PubMed:18376233]
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BackgroundThe expression of platelet-derived growth factor, a potent mitogen, and its receptor both in tissue and serum correlate with the severity of liver cirrhosis. Over-expression of platelet-derived growth factor has been demonstrated in human hepatocellular carcinoma (HCC) tumors and cell lines. Imatinib, a potent inhibitor of BCR-ABL and c-kit, also inhibits the platelet-derived growth factor receptor tyrosine kinase. The trial was designed to assess the efficacy and safety of imatinib in patients with unresectable HCC.MethodsEligibility criteria consisted of HCC patient over the age of 18 with reasonable organ function, unresectable but measurable disease, not candidates for chemoinfusion, and a performance status of 0 to 2. Imatinib was started at 300 mg/d orally with 100 mg/wk dose escalation up to 800 mg/d if toxicity permitted.ResultsFifteen patients, median age 58 years, were enrolled and treated with imatinib. Most, or 7, patients had hepatitis B virus as a risk factor for HCC, followed by hepatitis C virus in 3 patients. Metastatic disease (American Joint Committee on Cancer stage IV) was noted in 13 patients and locally advanced (stage III) in the remainder. The median dose-level of imatinib was 500 mg/d. Two patients had stable disease lasting more than 2 months. The remainder progressed within 2 months of initiation of imatinib. No grade 3 or 4 hematologic toxicity was observed. Two patients had grade 3 elevated liver function tests during treatment; otherwise, there was no other grade 3 or 4 nonhematologic toxicity noted.ConclusionAlthough toxicities were tolerable, imatinib as a monotherapy for the treatment of unresectable HCC has little, if any, significant efficacy. | Capdeville R, Krahnke T, Hatfield A, Ford JM, Van Hoomissen I, Gathmann I (2008)
Report of an international expanded access program of imatinib in adults with Philadelphia chromosome positive leukemias.
Annals of oncology : official journal of the European Society for Medical Oncology 19, 1320-1326 [PubMed:18344535]
[show Abstract]
BackgroundImatinib is a selective inhibitor of the BCR/ABL tyrosine kinase. The remarkable initial results of the first phase I clinical trial published in 1999 prompted the rapid initiation of large phase II trials. They also generated intense media coverage and significant interest from patients and clinicians and demand for access to imatinib before marketing approval. In response, a worldwide expanded access program (EAP) for imatinib was implemented in May 2000.PatientsIn total, 7380 patients with chronic myeloid leukemia (CML) and acute lymphoblastic leukemia failing prior therapies were enrolled in 106 centers in 34 countries.ResultsTime to progression and overall survival, as well as the safety profile, were similar to those observed in published phase II studies. At the end of the program, patients benefiting from treatment were continued on imatinib therapy by transferring to national health care systems or patient assistance programs.ConclusionThe imatinib EAP successfully provided therapy to patients with CML before marketing approval. The program provides an efficient framework for the development of global EAPs for innovative investigational anticancer agents in patients without a satisfactory therapeutic alternative. | Buyukbayrak EE, Ergen B, Karsidag YK, Kars B, Turan C, Argon D (2008)
Pregnancy complicated with chronic myelogeneous leukemia (CML) successfully treated with imatinib: a case report.
Archives of gynecology and obstetrics 278, 161-163 [PubMed:18193246]
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Pregnancy and cancer is a complex situation. The coincidence of chronic myelogeneous leukemia (CML) and pregnancy is an uncommon event, in part because CML occurs mostly in older age groups. The management of CML during pregnancy is a difficult problem because of the potential effects of the therapy on the mother and fetus. Imatinib is a relatively new drug in this era and it induces dramatic hematologic and cytogenetic responses in CML but it is not recommended for use during pregnancy or if the patient plans to conceive. In the literature there are very few reports of outcome of pregnancy conceived while on imatinib. In this report, we describe a successful pregnancy and labor under treatment of imatinib in a patient who was diagnosed with CML at the beginning of her pregnancy. | Chang H, Shih LY (2008)
Imatinib-induced tumor lysis syndrome: report of a case and review of the literature.
Chang Gung medical journal 31, 510-514 [PubMed:19097599]
[show Abstract]
Imatinib is a selective tyrosine kinase inhibitor which acts on breakpoint cluster region-Abelson fusion gene (BCR-ABL) positive leukemia including all phases of chronic myeloid leukemia and acute lymphoblastic leukemia. It may induce rapid apoptosis and subsequent tumor lysis syndrome. Only 3 cases of imatinib-induced tumor lysis syndrome have been reported. We herein described an additional patient with BCR-ABL (ela2) positive acute lymphoblastic leukemia who developed tumor lysis syndrome after 10-day treatment with imatinib. Experience in the current case suggests that preventive measures for tumor lysis syndrome, including allopurinol and hydration, should be taken for patients with high leukemia burden who receive imatinib therapy, and parameters of tumor lysis should be monitored in the early phase of therapy. | Heger U, Weitz J, Lordick F (2008)
[Indications for pre- and postoperative treatment with imatinib for gastrointestinal stromal tumors].
Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen 79, 630-637 [PubMed:18548219]
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Imatinib is a tyrosine kinase inhibitor directed against the KIT and the PDGF-alpha receptors. Imatinib has proven efficacy in the treatment of metastatic GIST with a response rate achieving 70%, but treatment with imatinib alone is not curative. The median progression-free survival is about 2 years. In locally advanced GIST, primary treatment with imatinib proved to be safe and feasible in several cohort studies. The goal of any curatively intended surgical treatment for GIST is R0 resection. Therefore, neoadjuvant treatment with imatinib can be recommended if tumor-free margin resection is doubtful. After R0 resection of GISTs with intermediate or high risk of relapse, preliminary data indicate that imatinib administered for at least 1 year reduces the risk of relapse and may improve the prognosis. However, no mature survival data from randomized studies have been published thus far. Therefore adjuvant treatment with imatinib is not yet approved nor is it a standard of care at this stage. The inclusion of patients with intermediate- and high-risk resected GIST into clinical studies is strongly recommended. | Soria A, Cario-André M, Lepreux S, Rezvani HR, Pasquet JM, Pain C, Schaeverbeke T, Mahon FX, Taïeb A (2008)
The effect of imatinib (Glivec) on scleroderma and normal dermal fibroblasts: a preclinical study.
Dermatology (Basel, Switzerland) 216, 109-117 [PubMed:18216472]
[show Abstract]
BackgroundScleroderma skin overexpresses the platelet-derived growth factor receptor beta-subunit (PDGFR-beta) in dermal vessels and PDGFR-beta messenger RNA in cultured fibroblasts. Moreover, increased levels of PDGF and stimulatory autoantibodies to PDGFR have been identified in the serum of scleroderma patients.ObjectiveImatinib being an inhibitor of tyrosine kinase receptors such as PDGFR, its effect on scleroderma fibroblasts was evaluated in vitro as a preclinical therapeutic step.MethodsThe effect of imatinib on fibroblasts grown from normal or involved/uninvolved scleroderma skin was studied by Western blot and the methyltetrazolium test. The pattern of distribution of PDGFR-beta in scleroderma versus normal skin was studied by immunohistochemistry.ResultsIn vitro, imatinib inhibited the proliferation of normal dermal and scleroderma fibroblasts at least partly via the inhibition of the phosphorylation of PDGFR. PDGFR-beta was expressed in the epidermis and adnexae in 5 lesional scleroderma biopsies and not in controls.ConclusionThis study suggests that imatinib can serve as therapy to limit dermal fibroblast proliferation in scleroderma. | Handolias D, McArthur GA (2008)
Imatinib as effective therapy for dermatofibrosarcoma protuberans: proof of concept of the autocrine hypothesis for cancer.
Future oncology (London, England) 4, 211-217 [PubMed:18407734]
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Cancer literature has consistently described autocrine loops involving growth factors to be important mechanisms for cellular transformation and proliferation in preclinical cancer models. Finally, convincing clinical data exist to implicate autocrine loops as central to the pathogenesis of a malignant condition, largely as a result of the recent development of inhibitors of protein tyrosine kinases important in cell signaling and growth. Although a rare condition, the study of patients with dermatofibrosarcoma protuberans (DFSP) is enriched by data demonstrating strong scientific rationale for its pathogenesis and susceptibility to molecular-based therapies. DFSP is a low-grade sarcoma that responds to treatment with imatinib, an inhibitor of the PDGF receptor tyrosine kinase. This treatment response illustrates the importance of autocrine/paracrine loops involving PDGF and its receptor as the key molecular target in DFSP. New insight into this fundamental biological mechanism sets the scene for the further development of molecular-targeted therapeutic options for cancer. | Bhattacharya S, Choudhury AK, Ravi S, Morrissey J, Mathew G (2008)
Six years survival on imatinib with no disease progression after diagnosis of metastatic duodenal gastrointestinal stromal tumour: a case report.
Journal of medical case reports 2, 110 [PubMed:18423008]
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IntroductionA duodenal Gastrointestinal Stromal Tumour (GIST) is a rare finding and until recently advanced disease had a poor prognosis. A PubMed search revealed no reports of more than five years survival of inoperable GIST on chemotherapy with WHO performance status zero.Case presentationA 68 year old female was diagnosed with unresectable GIST in the duodenum with metastasis to liver, pancreas and omentum in November 2001. She was commenced on imatinib mesylate (Glivec) chemotherapy. This case report was prepared from the medical records and radiology reports. She had good tolerance with stable disease. After six years her CT scan showed no disease progression and her WHO performance status was zero.ConclusionThis report supports the view that imatinib is a safe and effective drug in controlling disease progression in advanced metastatic GIST and plays an important role in improving the patient's quality of life. | Breccia M, Stefanizzi C, Cannella L, Latagliata R, Frustaci AM, Carmosino I, Santopietro M, Alimena G (2008)
Differences in hematological and non-hematological toxicity during treatment with imatinib in patients with early and late chronic phase chronic myeloid leukemia.
Leukemia & lymphoma 49, 2328-2332 [PubMed:19052981]
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Imatinib is a relatively specific inhibitor of the BCR/ABL tyrosine kinase, effective in chronic myeloid leukemia (CML). The aim of our study was to analyse the frequency and type of hematological and non-hematological adverse events in our series of late and early chronic phase patients with CML treated with imatinib and correlate the grade of hematological toxicity with the response obtained. Hematological events were seen in 59 out of 150 (39%) late chronic phase (CP) patients: of these, 24% experienced toxicity Grade 3-4. Of the 100 early CP patients, 26 (26%) had hematological adverse event: 7% experienced toxicity Grade 3-4 (p=0.0001). We found that only in early CP patients, the occurrence of hematological side effects of any grade within 6 months of therapy had a negative influence on cytogenetic response. We compared the incidence of non-hematological adverse events occurring in late and in early CP patients and found that in these latter, some side effects were more frequent, such as weight gain, periorbital edema, muscle cramps, skin rashes, diarrhea, weeping. On the contrary, we found that bone pain and hemorrhagic events were more common in late CP patients. Grade 3-4 adverse events were recorded at rates below 4% and decreased over time: in late CP patients hemorrhages and muscle cramps were the most common side effects of Grade 3-4, whereas in early CP patients, the most frequent events were nausea, weight gain and cutaneous rash. We have observed that hematological and non-hematological side effects during imatinib therapy are different among late and early CP patients and that severe hematological toxicity may influence cytogenetic response only in early CP patients. | Meera V, Jijina F, Shrikande M, Madkaikar M, Ghosh K (2008)
Twin pregnancy in a patient of chronic myeloid leukemia on imatinib therapy.
Leukemia research 32, 1620-1622 [PubMed:18420270]
[show Abstract]
Imatinib is a tyrosine kinase inhibitor and is now used regularly in chronic myeloid leukaemia therapy in chronic phase with great success. This drug due its very nature of action is suspected to be teratogenic hence the patients are counseled not to get pregnant while on this drug. However in world literature few normal pregnancies have been reported in patients on Imatinib therapy, though no twin pregnancy has been reported on this medication. We report here the birth of normal mono-ovular mono-chorionic twin while the patient is on imatinib during conception and early pregnancy for chronic myeloid leukaemia. | Declèves X, Bihorel S, Debray M, Yousif S, Camenisch G, Scherrmann JM (2008)
ABC transporters and the accumulation of imatinib and its active metabolite CGP74588 in rat C6 glioma cells.
Pharmacological research 57, 214-222 [PubMed:18337118]
[show Abstract]
Imatinib (Glivec, Gleevec, STI571) is a small tyrosine kinase inhibitor that is currently in phase II clinical trials in patients with recurrent glioblastoma. Its therapeutic benefit is minimal, although it is greater in some patients when combined with hydroxyurea. Imatinib is transported by human and rodent ATP-binding cassette (ABC) transporters like P-glycoprotein (Pgp) and the breast cancer resistance protein (BCRP). We have investigated whether ABC transporters determine the pharmacokinetics of imatinib and its pharmacological active metabolite CGP74588 in rat C6 glioma cells. ABC transporter expressions were measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). C6 cells express high concentrations of the Pgp-encoding gene Mdr1b and a 10-fold smaller amount of the Pgp-encoding gene Mdr1a. The relative expression of ABC transporter genes are: Mdr1b>Mrp4>Mrp1>Mrp5>Mdr1a>Mrp3>Mrp2>Bcrp. The accumulation of imatinib into C6 cells increased linearly with the extracellular concentration of imatinib (0.5-50microM) and was not increased by zosuquidar (selective Pgp inhibitor) or elacridar (inhibitor of both Pgp and Bcrp). In contrast, there was less CGP74588 than imatinib in C6 cells and its concentration increased with the extracellular concentration in a sigmoid fashion. Lastly, 10microM valspodar (selective Pgp inhibitor), elacridar and zosuquidar all increased the accumulation of CGP74588 by 2.5-fold. Thus CGP74588 is readily transported by the Pgp in rat C6 gliomas cells, which raises the question of the role of Pgp in the resistance of recurrent glioblastomas to imatinib. | (2008)
Imatinib: new indication. New indications, but not robust evidence.
Prescrire international 17, 91-94 [PubMed:18623899]
[show Abstract]
(1) Imatinib, a tyrosine kinase inhibitor, was first marketed for the treatment of chronic myeloid leukaemia and some gastrointestinal stromal tumours. Its indications have gradually expanded over the years. (2) There is no consensus treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia. In a trial comparing imatinib versus chemotherapy as initial treatment for 55 patients, the haematological response rate was higher with imatinib. Non-comparative trials provided haematological response rates of about 90%, but it is not known whether or not this translates into a survival advantage. In three non-comparative trials including patients with relapsed or refractory disease after chemotherapy, 50% of patients showed a survival time of at least 7 months. In the absence of any direct comparisons, we do not know if this represents an improvement over the results obtained with the best palliative care. (3) The only potential cure for myelodysplastic syndromes is allogeneic haematopoietic stem cell transplantation but this is not always feasible. Some myelodysplastic syndromes are associated with myeloproliferation and PDGFR gene rearrangements; imatinib is the first drug available for these patients. The manufacturer has compiled data on 55 patients treated with imatinib. Most patients had a favourable haematological response, but no survival data were published. (4) The severity of the hypereosinophilic syndrome is highly variable. Forms associated with FIP1L1-PDGFRalpha gene rearrangements have a poor prognosis. Clinical evaluation of imatinib in this setting is based on a compilation of data concerning 176 treated patients. The haematological response rate was high in patients with the mutant gene, but it is not known whether this translated into increased survival. (5) Dermatofibrosarcoma protuberans is a rare form of mainly localised skin cancer. Treatment is based on surgical excision but relapses are frequent. In one series, 9 out of 12 patients treated with imatinib had at least a partial tumour response, making surgical excision possible in 3 cases. (6) Imatinib has diverse and frequent adverse effects; nausea and vomiting, oedema, fluid retention, cutaneous disorders and heart failure. There is some evidence pointing to a risk of urologic cancers and altered bone metabolism. | (2008)
Imatinib: a second look. Longer follow-up in chronic myeloid leukaemia: clear advantages.
Prescrire international 17, 226-228 [PubMed:19415889]
[show Abstract]
(1) In 2002/2003, the clinical evaluation of imatinib, a tyrosine kinase inhibitor, in the treatment of chronic myeloid leukaemia left many questions unanswered. This article examines data published since then; (2) The only new data on first-line efficacy are the 5-year results of an unblinded trial comparing imatinib versus the interferon plus cytarabine combination. The survival rate was 89% with imatinib, versus about 70% in previous clinical trials of interferon plus cytarabine. Fewer than 2% of patients relapsed after responding to imatinib; (3) As second-line treatment for patients in the chronic phase, we now have non-comparative follow-up data on 532 patients in whom interferon had failed. At 5 years the overall survival rate was 79%, versus about 50% with standard treatments; (4) As second-line treatment for patients in the accelerated phase, we now have non-comparative follow-up data on 235 patients. After 3 years 55% of the patients were still alive, while the usual survival time is 3 to 18 months; (5) As second-line treatment of the blast crisis, we now have non-comparative follow-up data on 260 patients. After 3 years 14% of the patients were still alive, while the usual survival time for patients at this stage is 2 to 4 months; (6) The only new study is a non-comparative follow-up study of 50 children and adolescents aged 2 to 19 years treated with imatinib. The estimated 2-year survival rate was 84%. The haematological and cytogenetic response rates were similar to those reported in adults; (7) The initial clinical evaluation of imatinib showed that its main adverse effects were nausea and vomiting, oedema, fluid retention, muscle cramps, and cutaneous disorders. It was estimated that heart failure occurred in 1 to 10 per 1000 patients. A study of 54 patients confirmed the high incidence of cutaneous disorders. Cases of prostate and bladder cancer have been reported in patients treated with imatinib in France. A study of 16 patients suggests that imatinib might alter bone metabolism; (8) In France, treatment with imatinib costs about 25% more than the interferon plus cytarabine combination; (9) In practice, imatinib seems to increase survival time when used as a first-line or second-line treatment for patients in different phases of chronic myeloid leukaemia. Adverse effects must continue to be closely monitored. | Shepherd P, Dhanapala C, Maguire C, White J, Drummond M, Holyoake T, Johnson PR (2008)
Successful use of National Cancer Registry data to monitor the effective use of imatinib for treating chronic myeloid leukaemia.
Scottish medical journal 53, 8-12 [PubMed:18780518]
[show Abstract]
UnlabelledImatinib is a tyrosine kinase inhibitor, which selectively antagonises the BCR-ABL molecular pathway which causes chronic myeloid leukaemia (CML). Imatinib was first approved by the Scottish Medicines Consortium (SMC) in January 2002 with the recommendation that its use be audited. The cost of the drug has major financial implications for health resources.MethodsAll imatinib usage since its first prescription in Scotland in September 2000 to July 2003 was audited through pharmacy records and through the Scotland Leukaemia Registry (SLR), an existing national registry of patients with CML.ResultsOne hundred and four patients in Chronic Phase (CP), 36 in Accelerated Phase (AP) and five in Blast Phase (BP) received imatinib. The median duration of therapy was not reached for CFP 17 months for AFP and two months for BP patients. Major (complete) cytogenetic response rates were 74% (63%) and 38% (24%) respectively for CP and APR Overall survival for all CP patients from the start of imatinib therapy was 94% at one year, 91% at two years and 83% at three years. An audit of the effectiveness of the SLR as an auditing agency, showed complete registration in 95% of cases.ConclusionsWe believe such data collection should be an important ongoing resource for assessing outcomes in a rare form of leukaemia but one which already has major implications for health economics and will continue to do so given the future development of dual tyrosine kinase inhibitors for imatinib resistant cases. | Azuma M, Nishioka Y, Aono Y, Inayama M, Makino H, Kishi J, Shono M, Kinoshita K, Uehara H, Ogushi F, Izumi K, Sone S (2007)
Role of alpha1-acid glycoprotein in therapeutic antifibrotic effects of imatinib with macrolides in mice.
American journal of respiratory and critical care medicine 176, 1243-1250 [PubMed:17717205]
[show Abstract]
RationaleImatinib is an inhibitor of platelet-derived growth factor receptors. We have reported that treatment with imatinib inhibited bleomycin-induced pulmonary fibrosis in mice. However, late treatment with imatinib had no effect.ObjectivesTo clarify why imatinib had no antifibrotic effect when its administration was delayed, we focused on alpha(1)-acid glycoprotein (AGP), because it was reported to bind imatinib and mediate drug resistance.MethodsThe concentration of AGP in serum of mice and patients with idiopathic pulmonary fibrosis was measured by radial immunodiffusion testing. The effects of AGP in vitro were evaluated by assaying the growth of lung fibroblasts. We examined the combined effects of erythromycin (EM) or clarithromycin (CAM) on bleomycin-induced pulmonary fibrosis in mice.Measurements and main resultsAddition of AGP abrogated imatinib-mediated inhibition of the growth of fibroblasts. However, treatment with EM or CAM restored the growth-inhibitory effects of imatinib. The elevated level of AGP was detected in serum and lung homogenates in bleomycin-exposed mice and reached a plateau on Day 14. Imatinib alone did not ameliorate pulmonary fibrosis when treatment was started on Day 15, whereas coadministration of imatinib and EM or CAM significantly reduced the fibrogenesis via inhibition of the growth of fibroblasts in vivo. Serum levels of AGP were higher in patients with idiopathic pulmonary fibrosis than in healthy subjects.ConclusionsAGP is an important regulatory factor modulating the ability of imatinib to prevent pulmonary fibrosis in mice, and combined therapy with imatinib and EM or CAM might be useful for treatment of pulmonary fibrosis. | Govind Babu K, Attili VS, Bapsy PP, Anupama G (2007)
Imatinib-induced optic neuritis in a patient of chronic myeloid leukemia.
International ophthalmology 27, 43-44 [PubMed:17410337]
[show Abstract]
Imatinib is presently the commonest prescribes drug for patients of chronic myelogenous leukemia (CML) in chronic phase (CP) worldwide. Its ocular side effects are little known. Optic neuritis caused by this drug has not been reported (Medline search). We describe perhaps the first case of optic neuritis caused by this drug. | Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD (2007)
Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia.
Nature reviews. Cancer 7, 345-356 [PubMed:17457302]
[show Abstract]
Imatinib, a small-molecule ABL kinase inhibitor, is a highly effective therapy for early-phase chronic myeloid leukaemia (CML), which has constitutively active ABL kinase activity owing to the expression of the BCR-ABL fusion protein. However, there is a high relapse rate among advanced- and blast-crisis-phase patients owing to the development of mutations in the ABL kinase domain that cause drug resistance. Several second-generation ABL kinase inhibitors have been or are being developed for the treatment of imatinib-resistant CML. Here, we describe the mechanism of action of imatinib in CML, the structural basis of imatinib resistance, and the potential of second-generation BCR-ABL inhibitors to circumvent resistance. | Martínez-González MC, del Pozo J, Yebra-Pimentel MT, Pérez M, Almagro M, Fonseca E (2007)
Livedoid skin reaction probably due to imatinib therapy.
The Annals of pharmacotherapy 41, 148-152 [PubMed:17190842]
[show Abstract]
ObjectiveTo report 3 cases of skin rash with a peculiar livedoid pattern that were probably associated with imatinib therapy.Case summaryIn the first case, a 74-year-old male diagnosed with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), treated with imatinib 400 mg/day, developed a skin eruption with a livedoid pattern. Systemic corticosteroids were started, and skin lesions improved. The second case involved a 66-year-old male with Ph+ CML who was treated with imatinib 600 mg/day. After initiation of this treatment, he developed a skin rash with a livedoid pattern. The drug treatment was discontinued and then reintroduced. Topical corticosteroid treatment was started, resulting in total remission of the skin lesions. When the imatinib dose was progressively reintroduced, the skin lesions recurred. The patient died as a result of the progression of his disease. In the third case, a 43-year-old male with Ph+ acute lymphoblastic leukemia was treated with imatinib 600 mg/day. After a few days of treatment, the patient developed a skin rash with a livedoid pattern. He died as a result of probable septic shock.DiscussionImatinib is a tyrosine kinase receptor inhibitor that inhibits BCR/ABL tyrosine kinase. There have been several published articles on cutaneous adverse reactions related to imatinib therapy. The most common cutaneous adverse event of imatinib is a rash with variable clinical presentation. The Naranjo probability scale indicated a probable relationship between imatinib and the rash in all 3 cases reported here.ConclusionsAdverse reactions to imatinib that affect the skin occur frequently. They are strongly dose dependent, self-limiting, or easily managed by lowering the dose of imatinib and, if necessary, prescribing short-term therapy with a systemic corticosteroid. Clinicians should monitor patients taking imatinib and institute treatment quickly if a rash develops. | Hamaï A, Richon C, Meslin F, Faure F, Kauffmann A, Lecluse Y, Jalil A, Larue L, Avril MF, Chouaib S, Mehrpour M (2006)
Imatinib enhances human melanoma cell susceptibility to TRAIL-induced cell death: Relationship to Bcl-2 family and caspase activation.
Oncogene 25, 7618-7634 [PubMed:16983347]
[show Abstract]
In order to define genetic determinants of primary and metastatic melanoma cell susceptibility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), we have applied oligonucleotide microarrays to TRAIL-sensitive primary T1 cells and TRAIL-resistant metastatic G1 cells treated or not with TRAIL. T1 and G1 cells are isogenic melanoma cell subclones. We examined 22 000 spots, 4.2% of which displayed differential expression in G1 and T1 cells. Cell susceptibility to TRAIL-mediated apoptosis was found to be correlated with gene expression signatures in this model. Some of the differentially expressed genes were identified as involved in ATP-binding and signaling pathways, based on previously published data. Further analysis provided evidences that c-kit was overexpressed in G1 cells while it was absent in T1 cells. The c-kit inhibitor, imatinib, did not restore TRAIL sensitivity, excluding a role for c-kit in TRAIL resistance in G1 cells. Surprisingly, imatinib inhibited cell proliferation and TRAIL-mediated apoptosis in melanoma cells. We investigated the possible involvement of several molecules, including c-ABL, platelet-derived growth factor receptor (PDGFR), cellular FADD-like interleukin-1 alpha-converting enzyme-like inhibitory protein (c-FLIP)(L/S), Fas-associated DD kinase, p53, p21(WAF1), proteins of B-cell leukemia/lymphoma 2 (Bcl-2) family and cytochrome c. Imatinib did not modulate the expression or activation of its own targets, such as c-ABL, PDGFRalpha and PDGFRbeta, but it did affect the expression of c-FLIP(L), BCL2-associated X protein (Bax) and Bcl-2. Moreover, c-FLIP(L) knockdown sensitized T1 cells to TRAIL-mediated apoptosis, with a sensitivity similar to that of cells previously treated with imatinib. More notably, we found that the resistance to TRAIL in G1 cells was correlated with constitutive c-FLIP(L) recruitment to the DISC and the inhibition of caspase 8, 3 and 9 processing. Moreover, c-FLIP(L) knockdown partly restored TRAIL sensitivity in G1 cells, indicating that the expression level of c-FLIP(L) and its interaction with TRAIL receptor2 play a crucial role in determining TRAIL resistance in metastatic melanoma cells. Our results also show that imatinib enhances TRAIL-induced cell death independently of BH3-interacting domain death agonist translocation, in a process involving the Bax:Bcl-X(L) ratio, Bax:Bcl-X(L)/Bcl-2 translocation, cytochrome c release and caspase activation. Our data indicate that imatinib sensitizes T1 cells by directly downregulating c-FLIP(L), with the use of an alternative pathway for antitumor activity, because PDGFRalpha is not activated in T1 cells and these cells do not express c-kit, c-ABL or PDGFRbeta. Caspase cascade activation and mitochondria also play a key role in the imatinib-mediated sensitization of melanoma cells to the proapoptotic action of TRAIL. | Oertel S, Krempien R, Lindel K, Zabel A, Milker-Zabel S, Bischof M, Lipson KE, Peschke P, Debus J, Abdollahi A, Huber PE (2006)
Human glioblastoma and carcinoma xenograft tumors treated by combined radiation and imatinib (Gleevec).
Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] 182, 400-407 [PubMed:16826359]
[show Abstract]
Background and purposeImatinib (Gleevec, Glivec) is an inhibitor of alpha- and beta-platelet-derived growth factor receptors and other tyrosine kinases, that are also associated with the function of growth factors. Imatinib has been approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors and is under investigation for the therapy of several other malignant tumors. Since radiotherapy is an important treatment option in many tumors, combined effects of imatinib and radiation were analyzed here.Material and methodsIn vitro, U87 cells (human glioblastoma), A431 cells (human epidermoid carcinoma), and HUVECs (human umbilical venous endothelial cells) were treated with imatinib alone and in combination with radiation. Clonogenic survival and cell proliferation were determined with and without additional radiation (0-10 Gy). In vivo, U87 and A431 cells (5 x 10(6)) were subcutaneously injected into hind limbs of balb c nu/u mice. Drug and radiation treatments started on day 0 when tumor volumes were approximately 400-500 mm(3). Tumors were treated with 5 x 5 Gy (U87) or 6 x 5 Gy (A431) on consecutive days from day 0. Imatinib was administered orally via the mouse diet starting on day 0 until the end of observation. Tumor growth and microvessel density (CD31 IHC) were analyzed.ResultsIn vitro, imatinib increased radiosensitivity of U87 and A431 tumor cells as well as HUVECs in both clonogenic and cell number/proliferation assays. The enhancement of radiosensitivity in HUVECs was comparable to that observed in the tumor cells. In vivo, the concurrent and continuous administration of imatinib increased tumor growth delay of fractionated radiotherapy in the carcinoma and the glioblastoma models at reduced microvessel densities. No apparent additional toxicity by the combination of radiation and imatinib versus monotherapies was observed in terms of weight, skin, or general behavior.ConclusionImatinib (Gleevec), a "molecular targeted" approved drug for human malignancies, can enhance the tumor growth reduction induced by fractionated radiotherapy in glioblastoma and carcinoma models. The data provides a rationale to further investigate the combination. | Peng B, Lloyd P, Schran H (2005)
Clinical pharmacokinetics of imatinib.
Clinical pharmacokinetics 44, 879-894 [PubMed:16122278]
[show Abstract]
Imatinib is a potent and selective inhibitor of the protein tyrosine kinase Bcr-Abl, platelet-derived growth factor receptors (PDGFRalpha and PDGFRbeta) and KIT. Imatinib is approved for the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST), which have dysregulated activity of an imatinib-sensitive kinase as the underlying pathogenetic feature. Pharmacokinetic studies of imatinib in healthy volunteers and patients with CML, GIST and other cancers show that orally administered imatinib is well absorbed, and has an absolute bioavailability of 98% irrespective of oral dosage form (solution, capsule, tablet) or dosage strength (100 mg, 400 mg). Food has no relevant impact on the rate or extent of bioavailability. The terminal elimination half-life is approximately 18 hours. Imatinib plasma concentrations predictably increase by 2- to 3-fold when reaching steady state with 400mg once-daily administration, to 2.6 +/- 0.8 microg/mL at peak and 1.2 +/- 0.8 microg/mL at trough, exceeding the 0.5 microg/mL (1 micromol/L) concentrations needed for tyrosine kinase inhibition in vitro and leading to normalisation of haematological parameters in the large majority of patients with CML irrespective of baseline white blood cell count. Imatinib is approximately 95% bound to human plasma proteins, mainly albumin and alpha1-acid glycoprotein. The drug is eliminated predominantly via the bile in the form of metabolites, one of which (CGP 74588) shows comparable pharmacological activity to the parent drug. The faecal to urinary excretion ratio is approximately 5:1. Imatinib is metabolised mainly by the cytochrome P450 (CYP) 3A4 or CYP3A5 and can competitively inhibit the metabolism of drugs that are CYP3A4 or CYP3A5 substrates. Interactions may occur between imatinib and inhibitors or inducers of these enzymes, leading to changes in the plasma concentration of imatinib as well as coadministered drugs. Hepatic and renal dysfunction, and the presence of liver metastases, may result in more variable and increased exposure to the drug, although typically not necessitating dosage adjustment. Age (range 18-70 years), race, sex and bodyweight do not appreciably impact the pharmacokinetics of imatinib. | Jones RL, Judson IR (2005)
The development and application of imatinib.
Expert opinion on drug safety 4, 183-191 [PubMed:15794712]
[show Abstract]
The hallmark characteristics of cancer include an unrestrained proliferation involving activation of growth signals, loss of negative regulation and dysfunctional apoptotic pathways. Targeting abnormal cell signalling pathways should provide a more selective approach to cancer treatment than conventional cytotoxic chemotherapy. Tyrosine kinases play an essential role in the signalling pathways involved in the control of cellular proliferation and growth. Imatinib is a small-molecule tyrosine kinase inhibitor of the ABL fusion gene, platelet derived growth factor receptors (PDGFR) and KIT. This agent has demonstrated considerable activity in chronic myeloid leukaemia (CML) by inhibiting the BCR-ABL fusion protein and gastrointestinal stromal tumours (GISTs), which are predominantly driven by activating mutations in KIT. A number of other rare conditions are also responsive, for example, dermatofibrosarcoma protuberans, which is driven by a chromosomal translocation involving PDGF-B and Col1A1, resulting in overexpression of PDGF-B, and hypereosinophillic syndrome, which can be caused by activating PDGFR mutations. The pivotal registration study for newly diagnosed CML was a large randomised trial comparing 400 mg/day of imatinib to a combination of IFN-alpha and cytarabine, which demonstrated a significantly higher complete haematological and cytogenetic response rate in the imatinib arm. In the case of GIST a randomised study in patients with inoperable or metastatic disease explored doses of 400 - 600mg and reported a response rate of > 50% in each arm plus disease stabilisation and an improvement in performance status. Large randomised trials have subsequently been performed, comparing 400 with 800mg/day. The first to report indicates that the larger dose is associated with improved progression-free survival, although it is not yet known whether or not this will translate into a difference in overall survival. The most common KIT mutation involves exon 11 and is associated with a statistically significant better response and prognosis compared with other mutations or no detectable mutations. Mutational analysis is likely to become increasingly important in the selection of patients for neoadjuvant and adjuvant treatment and in helping to understand the nature of acquired resistance. | Lai IR, Hu RH, Chang KJ (2005)
Is imatinib justified as an adjuvant chemotherapy for patients with recurrent gastrointestinal stromal tumors.
Hepato-gastroenterology 52, 826-828 [PubMed:15966213]
[show Abstract]
Imatinib, an inhibitor of the tyrosine kinase activity of c-kit, was used as an adjuvant chemotherapy in two patients who underwent curative surgery for recurrent gastrointestinal stromal tumors. One patient has maintained tumor-free survival for 12 months, while the other had rapid recurrence and metastasis of tumors 3 months after he discontinued the drug. The indication and effects of imatinib for prevention of recurrence of GIST after ablative surgery were discussed. | Shimojima N, Nakaki T, Morikawa Y, Hoshino K, Kitajima M (2005)
Imatinib blocks spontaneous mechanical activities in the adult mouse small intestine: possible inhibition of c-Kit signaling.
Pharmacology 74, 95-99 [PubMed:15722647]
[show Abstract]
Interstitial cells of Cajal (ICCs) are postulated to serve as pacemakers that physiologically generate electrical slow waves in the gastrointestinal tract. Imatinib is a novel and potent inhibitor of c-Kit tyrosine kinase and a new therapeutic agent for gastrointestinal stromal tumors (GIST) which presumably arise from ICCs. The effects of imatinib on the basal rhythmic mechanical activities of small intestinal circular muscles were investigated in ring preparations of the gut. The small intestinal rings of BALB/c mice exhibited spontaneous contractile activity at a rate of 40.8 +/- 4.9 contractions/min. Imatinib (1- 81 micromol/l) dose-dependently abolished spontaneous contractile activity in the 9- to 27-micromol/l concentration range. Contraction was restored by washing imatinib out with a fresh buffer. High K(+)-induced contraction was not affected by imatinib, suggesting that the drug does not have nonspecific inhibitory actions on the smooth muscles. The small intestinal rings of adult W/W(v)mice, which lack a functional c-Kit activity,exhibited only small and irregular spontaneous contractions. These results demonstrate that imatinib affects bowel contractions, and suggest that the c-Kit signaling of ICCs plays an essential role in the spontaneous movements in circular muscles of the mouse small intestine. | Mohty M, Jourdan E, Mami NB, Vey N, Damaj G, Blaise D, Isnardon D, Olive D, Gaugler B (2004)
Imatinib and plasmacytoid dendritic cell function in patients with chronic myeloid leukemia.
Blood 103, 4666-4668 [PubMed:14715630]
[show Abstract]
Plasmacytoid dendritic cells (PDCs) are crucial effectors in innate immunity. In this study, we show that imatinib, a potent inhibitor of BCR/ABL tyrosine kinase activity, in the presence of Flt3-Ligand, could induce CD34+ progenitors from chronic myeloid leukemia (CML) to give rise in vitro to typical BDCA-2+ type I interferon-producing PDCs. The effect of imatinib on PDC generation was related to up-regulation of Flt3 on leukemic CD34+ progenitors. Moreover, patients with chronic myeloid leukemia (CML) who were in complete cytogenetic or molecular response after imatinib treatment restored their blood PDCs both quantitatively and functionally comparable to healthy donors, in contrast to patients not responding to imatinib, further confirming that disease response to imatinib is accompanied by restoration of PDC function in vivo. These findings provide evidence that response to imatinib is capable to restore some DC-related immune functions in CML that might be beneficial for long-term disease control. | Dressman MA, Malinowski R, McLean LA, Gathmann I, Capdeville R, Hensley M, Polymeropoulos MH, International Randomized Study of Interferon-alpha versus ST1571 Study Group (2004)
Correlation of major cytogenetic response with a pharmacogenetic marker in chronic myeloid leukemia patients treated with imatinib (STI571).
Clinical cancer research : an official journal of the American Association for Cancer Research 10, 2265-2271 [PubMed:15073101]
[show Abstract]
PurposeImatinib, an inhibitor of the Bcr-Abl tyrosine kinase, is indicated for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia. We examined genotypes from patients enrolled in the International Randomized Study of IFN-alpha versus STI571 in an attempt to identify factors that associate with cytogenetic response.Experimental designSixty-eight polymorphic loci in 26 genes were examined in a subset of 187 patients (imatinib-treated patients, n = 113; IFN + 1-beta-D-arabinofuranosylcytosine-treated patients, n = 74). Correlations between genotype and major cytogenetic response (MCyR) were examined by Fisher's exact tests. Multivariate and survival analyses were also performed.ResultsA significant association between MCyR and the rs2290573 polymorphism mapped to 15q22.33 was observed in imatinib-treated patients (P = 0.00037, Bonferroni corrected P = 0.025). Individuals with a CC genotype at this locus had a MCyR rate of 52% compared with individuals with a CT or TT genotype that had a MCyR rate of 89% (odds ratio, 6.72; 95% confidence interval, 1.51-29.91). In a multivariate analysis, the rs2290573 polymorphism was significant, whereas Sokal score was not. Time to progression analysis illustrated a significant difference based on genotype for the rs2290573 polymorphism.ConclusionsA significant association was identified between the genetic polymorphism rs2290573 and MCyR in imatinib-treated patients. This polymorphism is located in the intronic sequence of a putative gene with a tyrosine kinase domain. Multivariate analysis suggests that an individual's genotype for rs2290573 has more predictive value for MCyR than prognostic variables such as Sokal score. The clinical relevance of these results requires validation in future clinical trials. | Molnár L, Nagy A, Dávid M, Szomor A, Méhes G, Kovács G, Losonczy H (2004)
[Results of imatinib therapy in late-stage chronic myeloid leukemia after treatment with interferon-alpha].
Orvosi hetilap 145, 901-907 [PubMed:15170967]
[show Abstract]
BackgroundChronic myelogenous leukemia is characterised by the presence of Philadelphia translocation and consecutive expression of bcr-abl oncogene with enhanced tyrosine kinase activity, which is known to be the essential pathogenetic event in the disease. Imatinib (Glivec, formerly STI571) is a highly selective inhibitor of the bcr-abl tyrosine kinase which has shown a promising therapeutic activity in chronic myeloid leukemia as the first molecularly targeted antinoplastic treatment.MethodsBetween January 2001 and October 2001, 54 patients with chronic phase CML, resistant or intolerant to interferon-alpha were enrolled into the Novartis Expanded Access Study (Protocol 0113). Patients characteristics were as follows: male/female: 32/22, median age: 49 years (range: 22-75), median duration of disease: 44 months (range: 3-152). All patients received 400 mg imatinib orally.ResultsComplete hematologic response was obtained in 53 patients (96%) within 4 weeks. Major cytogenetic response (< 35% Ph+ metaphasis) was achieved after 6 months in 62.9%, and after 12 months in 64.8% of patients. Three patients progressed during the treatment (loss of complete hematologic response or cytogenetic response 1, blastic phase 2). The treatment was well tolerated, with mild side effects. Main non-hematologic side effects were weight gain and fluid retention.ConclusionsThe results confirm that imatinib is highly active in inducing complete hematologic response and major cytogenetic response in most patients who failed interferon-alpha. Treatment was well tolerated with rare and mild adverse events and impressive improvement of quality of life. | Aswald JM, Lipton JH, Aswald S, Messner HA (2002)
Increased IFN-gamma synthesis by T cells from patients on imatinib therapy for chronic myeloid leukemia.
Cytokines, cellular & molecular therapy 7, 143-149 [PubMed:14660054]
[show Abstract]
Decreased Type 1 cytokine production has been observed in T cells of patients with untreated chronic myeloid leukemia (CML). The important role of T cells and T-cell cytokines in the long-term control of CML is well established, for example in allogeneic stem-cell graft recipients. This study examined whether or not molecularly targeted therapy with imatinib, an inhibitor of the BCR-ABL tyrosine kinase, improved endogenous T-cell function in patients resistant to or intolerant of previous IFN-alpha therapy. Intracellular cytokine staining and detection by flow cytometry was used to analyze the expression of the T1 cytokine IFN-gamma in T cells. To secure independence from changes in white blood cell counts during treatment, a constant number of T cells was purified from the peripheral blood before analysis of the proportion of IFN-gamma synthesizing T cells. Twenty-nine patients with CML were tested before and after a median follow-up of 3 month on imatinib. In addition, late follow-up (past the median time to best cytogenetic response) of 15 patients were obtained Twenty-nine age- and gender-matched individuals were used as healthy controls. The frequency of IFN-gamma producing T cells in CML patients resistant to or intolerant to previous IFN-alpha therapy was lower than in healthy individuals (p=0.0181, Mann-Whitney test). Imatinib therapy led to a significant increase over pre-treatment values (p<0.0001, Mann-Whitney test). Late follow-up indicated that the increase was sustained in patients not in major cytogenetic response. In contrast, in major responders levels returned towards values comparable to healthy individuals. In conclusion, treatment with imatinib achieves a significant increase in Type 1 (IFN-gamma) cytokine-producing T cells in patients with CML. This is consistent with the view that enhanced T-cell function is achievable in patients with CML, even in the absence of allo-mechanisms. |
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2007-08-17
