Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of gastrointestinal stromal tumors (GISTs) in children is exceptionally low. However, during the last decade these tumors attracted increasing attention, because they were found to express the cell surface transmembrane receptor kit (CD117) that has tyrosine kinase activity. This tyrosine kinase can be semi-selectively inhibited by signal transduction inhibitors such as imatinib mesylate (Glivec), which is a competitive inhibitor of c-kit, c-abl, platelet-derived growth factor receptor-alpha (PDGFR-alpha) and PDGFR-beta, and abl-related gene (arg). The authors present the clinical, radiographic, and pathological findings of 4 children who were diagnosed with gastric GIST. One of them had an incomplete Carney triad including GIST and mediastinal paraganglioma. All 4 patients presented with anemia and anemia-related symptoms and underwent total resection of the tumor. One patient received additional chemotherapy (in the pre-imatinib era) and 2 patients received a short course of imatinib mesylate. With a follow-up of 116, 55, 23, and 10 months all patients are alive in first complete continuous remission. In children and adolescents, particularly in female patients, GISTs should be included in the differential diagnosis of anemia secondary to gastrointestinal hemorrhage. Complete surgical resection is the mainstay of treatment for this tumor, with imatinib mesylate restricted to patients with advanced or metastatic tumors. Since late recurrences (up to 30 years following initial diagnosis) are reported, a life-long follow-up is mandatory in these patients.
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PMID:Clinical, radiological, and pathological findings in four children with gastrointestinal stromal tumors of the stomach. 1745 92

Sorafenib is an orally available multikinase inhibitor active on vascular endothelial growth factor receptor-2 and -3, platelet-derived growth factor receptor-beta, B-RAF, C-RAF, flt3 and C-Kit. Phase I studies showed its activity on renal cell carcinoma (RCC) and other neoplasms and identified the schedule of 400 mg (two tablets) b.i.d. as better tolerated and potentially active. The original design selected for the principal phase II trial, randomization discontinuation trial, showed the particular activity profile of this drug: low objective response rates but significant increases in progression-free survival [PFS, which frequently translate in increased overall survival (OS)]. A pattern of response completely agrees with an antiangiogenic (cytostatic) agent. The potential efficacy of sorafenib was confirmed in immunotherapy-refractory advanced RCC cases by 'TARGETs', the largest randomized double-blind study ever carried out in kidney cancer. With a doubled PFS, a trend in OS and a modest toxicity profile, mainly grade 1-2 skin toxicity and diarrhea, sorafenib has been recently approved from the Food and Drug Administration and European Agency for the Evaluation of Medicinal Products for the second-line treatment of advanced RCC. Numerous trials are ongoing to test new schedules and drug combinations, while promising results were recently achieved also in hepatocellular carcinoma. With drugs such as sorafenib, angiogenesis could become an Achilles's heel for RCC.
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PMID:Protein kinase inhibitors in the treatment of renal cell carcinoma: sorafenib. 1759 26

With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.
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PMID:Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. 1762 Apr 31

Rheumatoid arthritis (RA) is a chronic inflammatory disease that is associated with joint destruction. Imatinib mesylate (imatinib) is an inhibitor that specifically targets a set of protein tyrosine kinase, such as abl, c-kit, and platelet-derived growth factor receptor (PDGFR) and it is widely used to treat chronic myeloid leukemia (CML). The purpose of the present study is to determine whether imatinib can provide benefit in the arthritis induced by anti-collagen type II antibody (CAIA) in mice, a model that provides an opportunity to study the effector inflammatory phase of arthritis without involving the priming phase of the immune responses. Mice treated with intraperitoneal administration of imatinib (1 or 10 mg/kg) prior to the development of CAIA displayed significant reductions in the severity of CAIA as assessed by arthritis score, histology, and synovial PDGF and vascular endothelial growth factor expression. In addition, treatment of the mice that had developed CAIA with intraperitoneal administration of imatinib (1 or 10 mg/kg) inhibited the progression of arthritis as assessed by those parameters. These results suggest that imatinib prevents and treats CAIA. Imatinib may thus have both a preventive and therapeutic potential for the joint inflammation at the effector stage of RA.
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PMID:Imatinib mesylate both prevents and treats the arthritis induced by type II collagen antibody in mice. 1769 64

Profibrogeneic cytokines contribute to the accumulation of myofibroblasts in the lung interstitium in idiopathic pulmonary fibrosis (IPF). Imatinib mesylate, a tyrosine kinase inhibitor specific for Abl, platelet-derived growth factor receptor (PDGFR) and c-Kit tyrosine kinases, has been shown to inhibit fibrosis and profibrotic signaling in mouse models of inflammation-mediated lung reactions. The authors tested imatinib mesylate in vivo in a mouse model of crocidolite asbestos-induced progressive fibrosis. The ability of imatinib mesylate to inhibit profibrogeneic cytokine-induced human pulmonary fibroblast migration was tested in vitro and the expression of its target protein tyrosine kinases was assessed with immunofluorescence. In vivo, 10 mg/kg/day imatinib mesylate inhibited histological parenchymal fibrosis and led to a decrease in collagen deposition, but had no significant effect on asbestos-induced neutrophilia. However, 50 mg/kg/day imatinib mesylate did not inhibit collagen deposition. In vitro, IPF fibroblasts expressed Abl, PDGFR-alpha, PDGF-beta, but not c-Kit, and 1 microM imatinib mesylate inhibited profibrogeneic cytokine-induced IPF fibroblast migration. These results suggest that imatinib mesylate is a potential and specific inhibitor of fibroblast accumulation in asbestos-induced pulmonary fibrosis.
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PMID:Imatinib mesylate inhibits fibrogenesis in asbestos-induced interstitial pneumonia. 1784 62

Growth, survival and differentiation of hematopoietic cells are regulated by the interactions between hematopoietic growth factors and their receptors. The defect in these interactions results in a failure of hematopoiesis, while aberrantly elevated and/or sustained activation of these signals cause hematologic malignancies. Among them, constitutively activating mutations of the receptor tyrosine kinases (RTKs), such as c-Kit, platelet-derived growth factor receptor (PDGFR) and FLT3, are often involved in the pathogenesis of various types of hematologic malignancies. Constitutive activation of RTKs is provoked by several mechanisms including chromosomal translocations and various mutations involving their regulatory regions. Chromosomal translocations commonly generate chimeric proteins consisting of the cytoplasmic domain of RTKs and the dimerization or multimerization motif of the fusion partner, resulting in the constitutive dimerization of RTKs. On the other hand, missense, insertion or deletion mutations in the regulatory regions, such as juxtamembrane domain, activation loop, and extracellular domain, also cause constitutive activation of RTKs mainly by preventing the auto-inhibitory regulation. Oncogenic RTKs activate downstream signaling molecules such as Ras/MAPK, PI3-K/Akt/mTOR, and STATs as well as ligand-activated wild type RTKs. However, their signals are quantitatively and qualitatively different from wild type RTKs. Based on these findings, several agents that target oncogenic RTKs or their downstream molecules have been developed: imatinib and FLT3 inhibitors for RTKs themselves, farnesyltransferase inhibitors, mTOR inhibitors and MEK inhibitors for the downstream signaling molecules. As promising results have been obtained in several clinical trials using these agents, the establishment of these molecular targeted agents is expected.
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PMID:Roles for deregulated receptor tyrosine kinases and their downstream signaling molecules in hematologic malignancies. 1817 85

We determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate, an inhibitor of the receptor tyrosine kinases platelet-derived growth factor receptor (PDGFR), the proto-oncogene product c-kit, and the fusion protein Bcr-Abl, when administered for 8 days in combination with temozolomide (TMZ) to malignant glioma (MG) patients. MG patients who had not failed prior TMZ were eligible to receive TMZ at a dose of 150-200 mg/m(2) per day on days 4-8 plus imatinib mesylate administered orally on days 1-8 of each 4-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing antiepileptic drugs (EIAEDs). The imatinib dose was escalated in successive cohorts of patients independently for each stratum. Imatinib, at doses ranging from 400 mg to 1,200 mg, was administered with TMZ to 65 patients: 52 (80%) with glioblastoma multiforme (GBM) and 13 (20%) with grade III MG. At enrollment, 34 patients (52%) had stable disease, and 33 (48%) had progressive disease; 30 patients (46%) were on EIAEDs. The MTD of imatinib for patients concurrently receiving or not receiving EIAEDs was 1,000 mg. DLTs were hematologic, gastrointestinal, renal, and hepatic. Pharmacokinetic analyses revealed lowered exposures and enhanced clearance among patients on EIAEDs. Among GBM patients with stable disease at enrollment (n=28), the median progression-free and overall survival times were 41.7 and 56.1 weeks, respectively. Imatinib doses up to 1,000 mg/day for 8 consecutive days are well tolerated when combined with standard TMZ dosing for MG patients. A subsequent phase 2 study is required to further evaluate the efficacy of this regimen for this patient population.
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PMID:Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: phase 1 trial in adults with malignant glioma. 1835 65

Treatments for metastatic renal cell carcinoma (MRCC) are limited. RCCs frequently overexpress epithelial growth factor receptor and express c-Kit and platelet-derived growth factor receptor-beta. Combination of interferon with tyrosine kinase inhibitors of epithelial growth factor receptor [gefitinib (Iressa)] or c-Kit and platelet-derived growth factor receptor-beta [imatinib (Gleevec)] was evaluated for efficacy and safety. Patients with MRCC received 12-week cycles of interferon [3 million units (MU) subcutaneously thrice in week 1 and 6 MU thrice weekly thereafter] and either gefitinib (500 mg daily) or imatinib (600 mg daily). The gefitinib/imatinib dose was reduced as needed owing to toxicity. The primary endpoint was objective tumor response. Secondary endpoints were time to tumor progression, overall survival, and safety. Seventeen patients were enrolled. Most had clear cell [36% (6/17)] or papillary [36% (6/17)] tumors. Most (n=14) were treated on the gefitinib arm, including two patients who crossed over from the imatinib arm after experiencing disease progression. Objective tumor responses were evaluable in 14 patients (82%). Of these 14, partial responses occurred in three (21%), stable disease in seven (50%), and progressive disease in four (29%). The most frequent treatment-related adverse events were skin rash, flu-like symptoms, and fatigue (both treatment arms); diarrhea (gefitinib arm only); and thrombocytopenia and leukopenia (imatinib arm only). Median time to tumor progression (range) for patients on the gefitinib arm only was 4.27 (1.13-15.97) months and median overall survival (range) was 11.42+ (1.13-29.07+) months. Combination of gefitinib with interferon safely delays progression of refractory MRCC. Further studies in this setting are warranted.
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PMID:Interferon-alpha in combination with either imatinib (Gleevec) or gefitinib (Iressa) in metastatic renal cell carcinoma: a phase II trial. 1841 19

We report a chronic myeloproliferative disease-unclassifiable (CMPD-U) patient who achieved hematological remission following imatinib mesylate (imatinib). Chromosomal and molecular analyses demonstrated no genetic abnormalities of c-abl, bcr-abl, c-kit or platelet-derived growth factor receptor (PDGFR) genes from hematopoietic cells. Although there has been one report of CMPD-U patient with chromosomal abnormalities of the PDGFR gene having complete hematologic responses upon treatment with imatinib, there have not been similar reports of patients without chromosomal abnormalities. This is the first case report of a CMPD-U patient with no chromosomal abnormalities who completely responded to treatment with imatinib.
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PMID:Successful treatment of chronic myeloproliferative disease-unclassifiable (CMPD-U) with no chromosomal abnormalities by imatinib mesylate. 1842 Dec

Pleuro-pulmonary solitary fibrous tumor (SFT) is a relatively uncommon mesenchymal neoplasm of uncertain histogenesis, unknown molecular features, and unpredictable clinical behavior. Although complete resection is universally accepted as the most important single prognostic factor, some clinicopathologic characteristics (gross appearance, tumor size, mitotic index, tumor necrosis, hypercellularity, and pleomorphism) are related to patient outcome, and a staging system based on these parameters with practical therapeutical implications has been recently proposed by de Perrot et al. Here, 88 pleuro-pulmonary SFTs were collected and clinicopathologic characteristics including de Perrot classification, patients' follow-up, p53 expression, and several "targetable" kinases [c-kit, v-raf murine sarcoma viral oncogene homolog B1, platelet-derived growth factor receptor (PDGFR)-alpha/beta, c-met, epidermal growth factor receptor (EGFR)] were retrospectively analyzed. Fifty-two cases (59%) had at least 1 clinicopathologic feature related to malignancy, whereas mortality and recurrences occurred in 10.2% and 18.2% of the cases, respectively. de Perrot staging and high p53 expression were significantly related to the conventional clinicopathologic prognostic features as well as to overall survival (OS) and disease-free survival (DFS) (P<0.001). At multivariate analysis, high p53 expression and tumor necrosis were the only parameters significantly associated with OS and DFS (P=0.017 and P=0.012, respectively). Immunohistochemical expression was frequently detected for PDGFR-alpha (97.7%), PDGFR-beta (86.5%), and hepatocyte growth factor receptor (96.6%), whereas missense mutations were only identified in 2 cases both involving PDGFR-beta (exons 18 and 20). We conclude that de Perrot stratification of SFT is a reliable prognostic indicator and merits consideration in view of its suggestions for the management of these tumors in daily practice. p53 expression may represent a valid and easy-to-test prognostic factor significantly related to OS and DFS. Although mutations of the corresponding genes are rare events in SFT, PDGFR-alpha/beta, and hepatocyte growth factor receptor tyrosine kinases should be further investigated given the availability of specific inhibitory molecules which might provide useful and novel therapeutical approaches for SFT patients.
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PMID:Pleuro-pulmonary solitary fibrous tumors: a clinicopathologic, immunohistochemical, and molecular study of 88 cases confirming the prognostic value of de Perrot staging system and p53 expression, and evaluating the role of c-kit, BRAF, PDGFRs (alpha/beta), c-met, and EGFR. 1875 43


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