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)

N-Phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas were found to be a novel class of potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase through synthetic modifications of a lead compound and structure-activity relationship studies. A representative compound 6ab, termed Ki8751, inhibited VEGFR-2 phosphorylation at an IC(50) value of 0.90 nM, and also inhibited the PDGFR family members such as PDGFRalpha and c-Kit at 67 nM and 40 nM, respectively. However, 6ab did not have any inhibitory activity against other kinases such as EGFR, HGFR, InsulinR and others even at 10000 nM. 6ab suppressed the growth of the VEGF-stimulated human umbilical vein endothelial cell (HUVEC) on a nanomolar level. 6ab showed significant antitumor activity against five human tumor xenografts such as GL07 (glioma), St-4 (stomach carcinoma), LC6 (lung carcinoma), DLD-1 (colon carcinoma) and A375 (melanoma) in nude mice and also showed complete tumor growth inhibition with the LC-6 xenograft in nude rats following oral administration once a day for 14 days at 5 mg/kg without any body weight loss.
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PMID:Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas. 1574 79

Leydig cell tumors are usually benign tumors of the male gonad. However, if the tumor is malignant, no effective treatments are currently available. Leydig cell tumors express platelet-derived growth factor (PDGF), kit ligand and their respective receptors, PDGFR and c-kit. We therefore evaluated the effects of imatinib mesylate (imatinib), a selective inhibitor of the c-kit and PDGFR tyrosine kinases, on the growth of rodent Leydig tumor cell lines in vivo and in vitro, and examined, in human Leydig cell tumor samples, the expression of activated PDGFR and c-kit and the mutations in exons of the c-kit gene commonly associated with solid tumors. Imatinib caused concentration-dependent decreases in the viability of Leydig tumor cell lines, which coincided with apoptosis and inhibition of proliferation and ligand-stimulated phosphorylation of c-kit and PDGFRs. Mice bearing s.c. allografts of a Leydig tumor cell line treated with imatinib p.o., had an almost complete inhibition of tumor growth, less tumor cell proliferation, increased apoptosis, and a lesser amount of tumor-associated mean vessel density compared with controls. No drug-resistant tumors appeared during imatinib treatment but tumors regrew after drug withdrawal. Human Leydig cell tumors showed an intense expression of the phosphorylated form of c-kit and a less intense expression of phosphorylated PDGFRs. No activating mutations in common regions of mutation of the c-kit gene were found. Our studies suggest that Leydig cell tumors might be a potential target for imatinib therapy.
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PMID:Imatinib mesylate inhibits Leydig cell tumor growth: evidence for in vitro and in vivo activity. 1575 88

Growth factor signals are propagated from the cell surface to intracellular processes that control critical functions such as growth, differentiation, angiogenesis, and inhibition of apoptosis via sequential kinase signaling. These kinases are receptor kinases, which are transmembrane proteins such as epidermal growth factor receptor or cytoplasmic kinases such as Src kinase. In malignancies, these signaling pathways are often exploited to optimize tumor growth and metastasis. Thus, they represent attractive targets for cancer therapy. This review will summarize current knowledge of the small-molecule multiple-kinase inhibitors in lung cancer therapy. These inhibitors generally hinder the phosphorylation of several protein kinases of membrane receptors, such as vascular endothelial growth factor receptors, platelet-derived growth factor receptors, the human epidermal growth factor receptor family, and cytoplasmic receptors such as c-Kit, Raf kinase, and FLT3. These inhibitors include ZD6474, SU11248, AEE 788, sorafenib, vatalanib, and AG-013736.
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PMID:Targeting multiple signal transduction pathways in lung cancer. 1615 18

The green fluorescence protein (GFP) from the UBI-GFP/BL6 transgenic line was bred into C57BL/6J-scid and C.B-17-scid mice for investigating host-tumor cell interactions. These mice express high levels of GFP under the control of the ubiquitin promoter in virtually all cells examined. In tumor tissue generated by implanting tumor cells in the GFP transgenic SCID mice, the tumor cells and tumor-associated murine host cells were clearly distinguished by GFP expression. A population of cells expressing the endothelial cell marker VEGFR-2/Flk-1, and the progenitor markers c-Kit and Sca-1, were incorporated into tumor tissue. The majority of the Flk-1-positive cells were hematopoietic-derived cells that coexpressed CD45. To investigate the contribution of bone marrow-derived cells to the formation of tumor vessels and stroma, tumor cells were implanted in nontransgenic SCID mice that received a bone marrow transplant from GFP-expressing SCID mice. Although GFP-positive cells were readily detected by histology in tumors taken from bone marrow transplanted animals, they were spatially isolated and lacked organization. In contrast, if tumors were implanted in nontransgenic SCID mice adjacent to a patch of transplanted GFP-expressing skin, these tumors recruited GFP-positive cells that organized into tumor vessels. The results demonstrate that hematopoietic-derived cells, including Flk-1+/CD45+ cells, readily colonized the tumor stroma but were minimally incorporated in the tumor vasculature. The majority of the tumor vessels were instead recruited from tissue adjacent to the tumor. The expression of Flk-1 on nonendothelial, tumor-associated host cells raises the possibility that VEGF antagonists, such as Avastin, could inhibit tumor growth by a mechanism involving hematopoietic-derived CD45+/Flk-1+ cells, in addition to direct suppression of endothelial cell function.
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PMID:Analysis of tumor-associated stromal cells using SCID GFP transgenic mice: contribution of local and bone marrow-derived host cells. 1639 72

Imatinib (Gleevec/STI-571/CGP57148B, Novartis) is a small-molecule, tyrosine kinase inhibitor developed to target BCR-ABL, c-Kit, and PDGF-R. Through inhibition of these oncogenic kinases, imatinib is effective in the treatment of BCR-ABL-positive leukemia, gastrointestinal stromal tumor, and hypereosinophilic syndrome, respectively. However, clinical success of imatinib is hampered by acquired resistance that may occur through several mechanisms including kinase domain mutation, target amplification, and activation of alternate signaling pathways. Strategies to overcome resistance have included targeting BCR-ABL stability and downstream signaling pathways important for tumor growth. Additional work has shown that new BCR-ABL kinase inhibitors with increased potency or alternate conformation-binding properties can target imatinib resistance. This review focuses on the mechanisms of imatinib resistance and the strategies currently being developed to overcome clinical resistance.
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PMID:Treating imatinib-resistant leukemia: the next generation targeted therapies. 1690 25

Leiomyomas are rare esophageal disorders, although among the benign esophageal neoplasms, they are the most common. Multiple leiomyomas are distinguished from esophageal leiomyomatosis, an extremely rare condition, which is associated with Alport syndrome, showing deletions and rearrangements of the COL4A5/COL4A6 gene. There are only a few reports of diffuse multilocular lesions. A 19-year-old man presented with upper gastrointestinal bleeding and diffuse abdominal pain. On endoscopy multiple nodules covered with intact mucosa were present, the largest tumor arising from the gastro-esophageal border infiltrating the cardia. Barium swallow demonstrated narrowing of the middle and lower esophagus with the upper third of the stomach filled by the tumor. Thorax and abdominal CT scans revealed infiltration of almost the total aboral esophagus by the tumor with compression of left and right bronchi. The infiltration reached the whole lesser curvature of the stomach. Endosonography showed multiple encapsulated nodules. Due to the extended tumor growth with infiltration of the upper third of the stomach, a total esophago-gastrectomy with reconstruction by colon interposition was performed. On histopathological examination multiple esophageal leiomyomas with infiltration of the proximal third of the stomach was shown. Immunohistochemically the tumor stained positive for desmin and sm-actin and negative for CD34 and c-kit. Genetic analysis ruled out a deletion of the COL4A5/COL4A6 locus on chromosome X that is linked with Alport syndrome-diffuse leiomyomatosis. Extended mutations in the COL4A5 gene, associated with Alport syndrome, to the COL4A6 gene, are required for the development of leiomyomatosis. In young patients with diffuse multinodular infiltration by encapsulated tumors, esophageal leiomyomatosis should be considered. If the proximal third of the stomach is infiltrated by the tumor an extended resection is necessary. Reconstruction procedures include colon interposition.
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PMID:Multiple giant leiomyomas of the esophagus and stomach. 1706 96

Angiogenesis and signaling through the RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinomas (HCC). Sorafenib (BAY 43-9006, Nexavar) is a multikinase inhibitor with activity against Raf kinase and several receptor tyrosine kinases, including vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit. In this study, we investigated the in vitro effects of sorafenib on PLC/PRF/5 and HepG2 HCC cells and the in vivo antitumor efficacy and mechanism of action on PLC/PRF/5 human tumor xenografts in severe combined immunodeficient mice. Sorafenib inhibited the phosphorylation of MEK and ERK and down-regulated cyclin D1 levels in these two cell lines. Sorafenib also reduced the phosphorylation level of eIF4E and down-regulated the antiapoptotic protein Mcl-1 in a MEK/ERK-independent manner. Consistent with the effects on both MEK/ERK-dependent and MEK/ERK-independent signaling pathways, sorafenib inhibited proliferation and induced apoptosis in both HCC cell lines. In the PLC/PRF/5 xenograft model, sorafenib tosylate dosed at 10 mg/kg inhibited tumor growth by 49%. At 30 mg/kg, sorafenib tosylate produced complete tumor growth inhibition. A dose of 100 mg/kg produced partial tumor regressions in 50% of the mice. In mechanism of action studies, sorafenib inhibited the phosphorylation of both ERK and eIF4E, reduced the microvessel area (assessed by CD34 immunohistochemistry), and induced tumor cell apoptosis (assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling) in PLC/PRF/5 tumor xenografts. These results suggest that the antitumor activity of sorafenib in HCC models may be attributed to inhibition of tumor angiogenesis (VEGFR and PDGFR) and direct effects on tumor cell proliferation/survival (Raf kinase signaling-dependent and signaling-independent mechanisms).
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PMID:Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. 1717 82

Gastrointestinal stromal tumors (GIST) have attracted basic scientists as well as clinicians in the last 10 years. The reason for this is explanation of the pathogenetic mechanism of tumor growth by activation of c-Kit protein, followed by a rationally designed suppressor, a drug named imatinib. It is the first successful therapy for solid tumors to date, although there are other ongoing studies of agents with targeted action on different molecules in different tumors. In 80% of patients there is a clinical benefit from imatinib trreatment. GIST shows great diversity in clinical presentation and some questions still remain, such as malignant potential and prognostic criteria in these tumors. Imatinib therapy demonstrates many favorable effects such as acceptable toxicity and relative mild side effects, excellent quality of life, good patient compliance, etc. There are ongoing trials of new agents designated for target molecules, which would hopefully show benefit after developing resistance to imatinib.
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PMID:[Gastrointestinal stromal tumors (GIST)--a paradigm of successful targeted therapy of solid tumors]. 1721 4

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

Heparanase is involved in tumor growth and metastasis. Because of its unique cleavage of heparan sulfate, which binds cytokines, chemokines and proteases, we hypothesized that heparanase is also involved in regulation of early stages of hematopoiesis. We report reduced numbers of maturing leukocytes but elevated levels of undifferentiated Sca-1(+)/c-Kit(+)/Lin(-) cells in the bone marrow (BM) of mice overexpressing heparanase (hpa-Tg). This resulted from increased proliferation and retention of the primitive cells in the BM microenvironment, manifested in increased SDF-1 turnover. Furthermore, heparanase overexpression in mice was accompanied by reduced protease activity of MMP-9, elastase, and cathepsin K, which regulate stem and progenitor cell mobilization. Moreover, increased retention of the progenitor cells also resulted from up-regulated levels of stem cell factor (SCF) in the BM, in particular in the stem cell-rich endosteum and endothelial regions. Increased SCF-induced adhesion of primitive Sca-1(+)/c-Kit(+)/Lin(-) cells to osteoblasts was also the result of elevation of the receptor c-Kit. Regulation of these phenomena is mediated by hyperphosphorylation of c-Myc in hematopoietic progenitors of hpa-Tg mice or after exogenous heparanase addition to wildtype BM cells in vitro. Altogether, our data suggest that heparanase modification of the BM microenvironment regulates the retention and proliferation of hematopoietic progenitor cells.
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PMID:Heparanase regulates retention and proliferation of primitive Sca-1+/c-Kit+/Lin- cells via modulation of the bone marrow microenvironment. 1833 74


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