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)

Imatinib mesylate (Gleevec) inhibits the BCR-ABL tyrosine kinase in chronic granulocytic leukemia. Previous studies have demonstrated that imatinib mesylate also inhibits the survival and functions of normal mast cells by interfering with the receptor tyrosine kinase for stem cell factor (SCF), c-kit, which is expressed by mast cells. Because mast cells extensively surround many types of cancer and contain powerful anticoagulants such as heparin, we investigated the effects of imatinib mesylate on blood clotting and tumor growth within subcutaneous implants of a mammary adenocarcinoma cell line (4T1) in BALB/c mice. After 5 days of oral treatment with 10 mg/kg of the drug, the average mass of the tumors in treated mice (198 +/- 42 mg, n = 5) was significantly (p < 0.05) greater than the average mass of the tumors from untreated (control) mice (60 +/- 23 mg, n = 5). Moreover, the tumors in the treated mice were frequently surrounded by large lakes of clotted blood that were not evident in tumors from the control mice. Accelerated growth and blood clotting were also observed in tumor-bearing mice treated with heparinase I enzyme to destroy endogenous mast cell heparin and in NDST-2 knockout mice in which there is a targeted disruption in the gene coding for mast cell heparin synthesis. We conclude that imatinib mesylate accelerated the growth and peri-tumoral blood clotting of implants of mammary adenocarcinoma in mice. These results suggest that imatinib mesylate may have significant effects on mast cells infiltrating tumors, in addition to its other biologic activities. Our results also indicate that the mechanism of this effect may be related to the anticoagulant properties of mast cell heparin.
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PMID:Acceleration of tumor growth and peri-tumoral blood clotting by imatinib mesylate (Gleevec). 1286 22

Receptor tyrosine kinase activation contributes to cell viability during cytotoxic therapy. The novel broad spectrum receptor tyrosine kinase inhibitor, SU11248, inhibits vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor, c-kit, and fetal liver tyrosine kinase 3. In this study, we maintained SU11248 plasma levels beyond the completion of radiotherapy to determine whether tumor regrowth can be delayed. The antiangiogenic effects of SU11248 were demonstrated using human umbilical vein endothelial cells in vitro. Apoptosis increased and clonogenic survival decreased when SU11248 was used in combination with radiation from 0 to 6 Gy on endothelial cells. In vivo tumor growth delay was increased in C57B6J mice with Lewis lung carcinoma or glioblastoma multiform (GL261) hind limb tumors. Mice were treated with daily i.p. injections (40 mg/kg) of SU11248 during 7 days of radiation treatment (21 Gy). Combined treatment with SU11248 and radiation significantly reduced tumor volume as compared with either treatment alone. Concomitant reduction in vasculature was confirmed using the dorsal vascular window model. The vascular length established using images taken from a consistent quadrant in the window show the combination therapy was more effective in destroying tumor vasculature than either treatment alone. SU11248 maintenance administration beyond the completion of radiotherapy results in prolongation of tumor control. In summary, SU11248 enhances radiation-induced endothelial cytotoxicity, resulting in tumor vascular destruction and tumor control when combined with fractionated radiotherapy in murine tumor models. Moreover, inhibition of angiogenesis well beyond radiation therapy may be a promising treatment paradigm for refractory human neoplasms.
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PMID:SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. 1287 99

Several signaling pathways have been recognized in normal c-kit-mediated signal transduction following stem cell factor (SCF) stimulation including Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK) and phosphoinositol 3-kinase (PI-3 K) pathways. In gastrointestinal stromal tumor (GIST), c-kit activation is considered to play a central role in its tumorigenesis. However, the signal transduction cascades specific for the SCF-independent c-kit activation in GIST remains to be elucidated. In this study, we examined for the expression of the activated form of STAT3 [phospho-STAT3 (tyr 705)] in eleven cases of GIST by immunohistochemistry. All GISTs had strong nuclear and variable cytoplasmic expression of phospho-STAT3 (tyr 705). Survival and proliferation of two established primary GIST cell lines with c-kit exon-11 mutations were then assessed for their response to inhibitors of c-kit (STI-571), JAK 2 (Tyrphostin AG490), MAPK kinase (PD98059) and PI-3 K(LY294002). GIST cells showed significant inhibition of proliferation and apoptosis when treated with STI571 or AG490 but not in cells treated with PD98059 or LY294002. Bcl-2 was expressed in all of the GIST cases (11 out of 11) and was down-regulated in the primary GIST cells following treatment with AG490. This study demonstrates that STAT3 is constitutively activated in GIST and JAK2 blockade leads to tumor growth inhibition and apoptosis indicating the involvement of the JAK/STAT signaling pathway in GIST cellular survival.
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PMID:Analysis of signal transducer and activator of transcription 3 (STAT3) in gastrointestinal stromal tumors. 1289

Modulation of the signaling pathways that are aberrant in cancer cells has the potential to provide an effective nontoxic approach to patient management in a broad range of cancers. This quest has taken a major leap forward with the demonstration that STI-571 (imatinib mesylate) induces clinical and molecular remissions in the majority of patients with interferon-refractory chronic myelogenous leukemia and gastrointestinal stromal tumors through inhibition of the Bcr/Abl fusion protein required for the initiation and progression of chronic myelogenous leukemia and inhibition of a mutant, activated c-kit present in gastrointestinal stromal tumors. Support for the concept of targeting products of fusion genes found in specific cancers was first provided by the efficacy of all-trans retinoic acid in acute promyelocytic leukemia where the RARalpha all-trans retinoic acid target is the target of multiple different chromosomal rearrangements. In breast cancer, trastuzumab, which alters the function of the HER2 proto-oncogene overexpressed in a portion of breast cancers, provides an additional example of targeting specific molecular aberrations present in cancer cells. Although the target for these signal transduction modulators is functional in normal cells, acceptable therapeutic indices sufficient to prevent tumor growth without unacceptable toxicities have been observed. Whether STI-571 and other signal transduction modulators also target the stroma, and specifically the neovasculature, in addition to the tumor remains an open question. The presence of the target in the cancer cells or in the surrounding stroma appears to be required but not sufficient for the action of molecular therapeutics. Thus, linking molecular diagnostics to identify patients where the target is amplified or activated and driving the pathophysiology of the patients' tumor to effective molecular therapeutics will be necessary to translate these concepts into approaches that will alter the outcome for breast cancer patients. This review will focus on the phosphatidylinositol 3-kinase pathway and novel molecules targeting this pathway to illustrate the questions and challenges underlying the implementation of molecular therapeutics in breast cancer.
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PMID:Linking molecular diagnostics to molecular therapeutics: targeting the PI3K pathway in breast cancer. 1461 30

Receptor and nonreceptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating certain types of cancer. Epidermal growth factor receptor (EGFR)-TK is a transmembrane receptor TK that is overexpressed or aberrantly activated in the most common solid tumors, including non-small cell lung cancer and cancers of the breast, prostate, and colon. Activation of the EGFR-TK enzyme results in autophosphorylation, which drives signal transduction pathways leading to tumor growth and malignant progression. Randomized clinical trials of the EGFR-TK inhibitor gefitinib have demonstrated clinical benefits in patients with advanced non-small cell lung cancer whose disease had previously progressed on platinum- and docetaxel-based chemotherapy regimens. Bcr-Abl is a constitutively activated nonreceptor TK enzyme found in the cytoplasm of Philadelphia chromosome-positive leukemia cells. STI571 (imatinib mesylate) inhibits the Bcr-Abl TK, blocks the growth of these leukemia cells, and induces apoptosis. STI571 also inhibits other TKs, including the receptor TK c-kit, which is expressed in gastrointestinal stromal tumors. As TK inhibitors become available for clinical use, new challenges include predicting which patients are most likely to respond to these targeted TK inhibitors. Additional clinical trials are needed to develop the full potential of receptor and nonreceptor TK inhibitors for cancer treatment.
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PMID:Activation of tyrosine kinases in cancer. 1465 31

The Kit receptor tyrosine kinase is a transmembrane receptor that is expressed in a variety of different tissues and mediates pleiotropic biological effects through its ligand stem cell factor (SCF). Sporadic mutations of Kit as well as autocrine/paracrine activation mechanisms of the SCF/Kit pathway have been implicated in a variety of malignancies, where its primary contribution to metastases is in enhancing tumor growth and reducing apoptosis. For example, Kit is frequently mutated and activated in gastrointestinal stromal tumors (GISTs) and there is ligand-mediated activation of Kit in some lung cancers. Kit is a convenient target in Kit-induced tumors and inhibition of this receptor with the small molecule drug Gleevec (imatinib mesylate, STI571) in GIST has shown dramatic efficacy. Unfortunately, past experience has demonstrated that chemotherapy of cancers with a single drug often leads to resistance of the cancer. Further understanding of the molecular mechanisms underlying Kit-mediated transformation is therefore important and may lead to the identification of further novel drug targets. These Kit-specific signaling pathways may then be targeted to overcome potential drug resistance. This review will focus on our understanding of the molecular mechanisms involved in transformation by Kit. The potential mechanisms by which Kit induces cellular transformation are described. We will also discuss the role and expression of Kit in various malignancies. Ultimately, the understanding of c-Kit biology, biochemistry, and mutational analysis will lead to better therapeutics.
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PMID:Targeting c-Kit mutations: basic science to novel therapies. 1503 37

The zinc-finger transcription factors Snail and Slug are involved in different processes controlling cell differentiation and apoptosis. They also appear to be involved in tumor progression. Their putative involvement in mammary gland development has not been specifically examined so far. Slug is expressed at a significant level in normal breast, and indirect evidence suggests it could be implicated in tubulogenesis. As an antiapoptotic agent, it could also protect epithelial cells from death during ductal lumen formation and during breast involution. In breast carcinomas, Snail transcription factors have been linked to tumor progression and invasiveness. Possible mechanisms include repression of the E-cadherin gene by Snail or Slug. However, it is not clear how this transcriptional activity is implicated in vivo. Other possible mechanisms involve maintenance of a plastic phenotype by Slug that could participate in local invasion of ductal carcinomas, and interference with apoptotic pathways that could contribute to global tumor growth and radioresistance. These processes probably also involve interactions with estrogen, EGF, or c-kit pathways.
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PMID:Roles of the transcription factors snail and slug during mammary morphogenesis and breast carcinoma progression. 1530 12

KIT ligand (KL) and its receptor, c-kit, are coexpressed in many types of cancer cells and have been implicated in tumor growth and angiogenesis. While Sertoli cell-specific regulation of the KL promoter has been well characterized, regulation in cancer cells remains to be elucidated. We recently reported microarray results demonstrating that increased high-mobility group (HMG) A1a protein expression correlates with increased KL transcription in MCF-7 human breast cancer cells. Sequence analysis indicates a potential for multiple HMGA1 binding sites within the human KL promoter. In order to better define the underlying molecular mechanisms that HMGA1 uses to facilitate malignant transformation of cancer cells, we have used a variety of methods to determine whether HMGA1a directly regulates the human KL promoter in breast and ovarian cancer cells. Our results indicate that: (i) KL promoter activity is significantly higher in MCF-7 cells overexpressing HMGA1a; (ii) HMGA1a protein binds to AT-rich regions of the KL promoter DNA both in vitro and in vivo; (iii) mutation of the AT-rich regions inhibits HMGA1a binding in vitro; and (iv) HMGA1a-specific inhibition significantly decreases transcription of KL in OCC1 human ovarian cancer cells. In addition, MCF-7 cells with transgenic HMGA1 overexpression stained positive for the KL protein by immunocytochemistry and immunohistochemistry, and were growth-inhibited by KL neutralization. The cumulative evidence indicates that HMGA1 positively regulates the human KL promoter in breast and ovarian cancer cells and implicates serum KL as a diagnostic marker for HMGA1-positive carcinomas.
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PMID:Human KIT ligand promoter is positively regulated by HMGA1 in breast and ovarian cancer cells. 1537 28

STI571, or imatinib, selectively inhibits BCR/ABL, PDGFR and c-kit kinase activity. It has been reported that a large proportion of small cell lung cancer (SCLC) cell lines and tumors express c-kit and that STI571 inhibits tumor cell growth. We therefore investigated the therapeutic efficacy of STI571, alone or combined with chemotherapy, in human SCLC cells or tumors xenografted into nude mice. The level of c-kit mRNA expression was variable in SCLC tumors (positive for 2 of 4 xenografts), and c-kit protein was not detected by immunohistochemistry. On the 4 xenografted tumors, PDGFRalpha and PDGFRbeta were not detected by immunohistochemistry. STI571 induced inhibition of proliferation of the SCLC6 cell line without inducing apoptosis; in contrast, in combination with etoposide or topotecan, the growth inhibition of SCLC6 cells induced by STI571 was increased, with apoptotic DNA fragmentation. Four human SCLC xenografts (SCLC6, SCLC61, SCLC74 and SCLC108) were transplanted into mice. After intraperitoneal injection of STI571, we observed 80%, 40% and 78% growth inhibition of SCLC6, SCLC61 and SCLC108 tumors, respectively, without any significant inhibition of SCLC74 tumor growth. In mice bearing responsive SCLC tumors, we observed an increase of growth inhibition induced by chemotherapy (etoposide + ifosfamide or topotecan) by concomitant and continuous administration of STI571, associated with an increase of toxic deaths. In SCLC6-bearing mice receiving sequential treatments, we observed a reduction of toxic deaths but a decrease of synergistic antitumor efficacy. In conclusion, the efficacy of STI571 alone in SCLC xenografted tumors was variable and did not depend on c-kit expression. Moreover, a significant increase of chemotherapy-induced growth inhibition was obtained by concomitant administration of STI571 that should be carefully investigated in SCLC patients.
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PMID:In vivo efficacy of STI571 in xenografted human small cell lung cancer alone or combined with chemotherapy. 1549 12

The angiogenesis inhibitor PTK 787/ZK 222584 (PTK/ZK) blocks all known VEGF receptor (VEGFR) tyrosine kinases, including the lymphangiogenic VEGFR3, in the lower nanomolar range. From a panel of 100 kinases only PDGFR, c-kit, and c-fms are inhibited beyond those in the nanomolar range. PTK/ZK functions as a competitive inhibitor at the ATP-binding site of the receptor kinase as shown here in kinetic experiments. The VEGF signal blockade in microvascular endothelial cells (MVEC) results in a blockade of MVEC proliferation (IC50=30 nM), without affecting the proliferation of normal tissue cells and tumor cells. The efficacy of PTK/ZK depends on its continuous presence within the endothelial target cells. Early removal attenuates its antiproliferative activity in vitro. Growth inhibition of endothelial cells is fully reversible as demonstrated by "washout" experiments. Without inhibiting tumor cell proliferation directly, PTK/ZK results in a significant retardation of tumor growth in a number of experimental tumor models of different tissue origin. Combination of PTK/ZK with an antiandrogen revealed additive effects on tumor-growth inhibition. Treatment efficacy was monitored both by tumor weight and by the determination of serum concentrations of the surrogate marker PSA. PTK/ZK is currently being investigated in patients with different solid tumor types for its therapeutic utility. Preliminary data from phase I/II clinical trials of PTK/ZK as a monotherapy suggested a positive safety and tolerability profile, which we interpret to be a consequence of the high selectivity of the drug for a limited number of kinases. Preliminary response, time to progression, and overall survival data were promising.1 Based on these encouraging results, PTK/ZK is currently in Phase III clinical trials for metastatic colorectal cancer.
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PMID:PTK 787/ZK 222584, a tyrosine kinase inhibitor of all known VEGF receptors, represses tumor growth with high efficacy. 1574 76


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