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)

A novel class of tyrosine kinase blockers represented by the tyrphostins AG1295 and AG1296 is described. These compounds inhibit selectively the platelet-derived growth factor (PDGF) receptor kinase and the PDGF-dependent DNA synthesis in Swiss 3T3 cells and in porcine aorta endothelial cells with 50% inhibitory concentrations below 5 and 1 microM, respectively. The PDGF receptor blockers have not effect on epidermal growth factor receptor autophosphorylation; weak effects on DNA synthesis stimulated by insulin, by epidermal growth factor, or by a combination of both; and over an order of magnitude weaker blocking effect on fibroblast growth factor-dependent DNA synthesis. AG1296 potently inhibits signaling of human PDGF alpha- and beta-receptors as well as of the related stem cell factor receptor (c-Kit) but has no effect on autophosphorylation of the vascular endothelial growth factor receptor KDR or on DNA synthesis induced by vascular endothelial growth factor in porcine aortic endothelial cells. Treatment by AG1296 reverses the transformed phenotype of sis-transfected NIH 3T3 cells but has no effect on src-transformed NIH 3T3 cells or on the activity of the kinase p60c-src(F527) immunoprecipitated from these cells. These potent and selective compounds represent leads for the development of novel agents to combat tumors driven by PDGF or to inhibit PDGF action in other diseases in which PDGF plays a key role, such as restenosis.
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PMID:Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. 795 56

The present review has summarized the expression, production and effects of the human interleukins (IL) 1-11 and myelopoietic colony stimulating factors (CSF) in the established myeloid leukemia cell lines and in cells from patients with acute myeloid leukemia as well as the oncogene expression reported in these myeloid leukemia cell lines. The genetic dissection of leukemic myelopoiesis may provide new perspectives for the control of myeloid leukemias. Based on their expression of phenotypic markers (e.g., surface antigens, cytochemical staining, etc.), myeloid cell lines can be further subdivided into myelogenous, monocytic, erythroid and megakaryoblastic leukemia cell lines. Due to the close relationship of erythroid and megakaryoblastic progenitor cells and to the existence of a probably common precursor cell giving rise to these two different cell lineages, many megakaryoblastic cell lines express erythroid markers (e.g., expression of hemoglobin or glycophorin A) and conversely cell lines with a predominant erythroid profile might display megakaryoblastic features (e.g., platelets peroxidase or glycoproteins CD41, CD42b or CD61). The recent cloning of the specific cytokine: thrombopoietin (TPO) and its receptor generated a strong interest in these particular myeloid cell lines that are discussed in more detail in the present review. Both normal and leukemic megakaryocytopoiesis are stimulated by granulocyte-macrophage colony stimulating factor (GM-CSF), IL-3, GM-CSF/IL-3 fusion protein, IL-6, IL-11 and TPO but inhibited by IL-4, interferon-alpha (IFN-alpha) and IFN-gamma. Human megakaryoblastic leukemia cell lines have common biological features: high expression of the megakaryocytic specific antigen (CD41); high expression of early myeloid antigens (CD34, CD33 and CD13); constitutive expression of IL-6 and platelet-derived growth factor; a complex karyotype picture; expression of c-kit (the stem cell factor receptor); growth-dependency or -stimulation by IL-3 and/or GM-CSF; and in vivo tumorigenicity in mice associated with marked fibrosis. Whereas numerous chemical and biologic agents induce granulocytic and/or monocytic differentiation of myeloid leukemia cell lines, only a few agents including phorbol myristate acetate, vitamin D3, IFN-alpha, IL-6 and thrombin have been reported to induce megakaryocytic differentiation in the megakaryoblastic leukemia cells.
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PMID:Interleukins and colony stimulating factors in human myeloid leukemia cell lines. 875 Jun 18

Primary effusion lymphoma (PEL) is a distinct clinicopathologic entity associated with Kaposi's sarcoma-associated herpes virus (KSHV). Several cytokines, including interleukin-6 (IL-6), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) may be important for survival of KS cells. However, little is known about the interaction of cytokines with KSHV-infected lymphocytes from PEL. Therefore, we investigated what cytokines were produced by KSHV-infected PEL cell lines (KS-1, BC-1, BC-2), what cytokine receptors were expressed by these cells, what response these cells had to selected cytokines, and what was the effect of IL-6 antisense phosphorothioated oligonucleotides. Reverse transcriptase-polymerase chain reaction (RT-PCR) and protein studies showed that these three cell lines produced IL-10, IL-6, and the receptors for IL-6. The granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1beta, IL-8, IL-12, bFGF, PDGF, and c-kit transcripts were not detected in the cell lines. High levels (0.7 to 5 ng/mL/10(6) cells/48 hours) of IL-6 protein were consistently detected in supernatants of the cell lines by enzyme-linked immunosorbent assay (ELISA) tests. In clonogenic assays, interferon-alpha (IFN-alpha) and IFN-gamma suppressed the clonal growth of the PEL cells, but GM-CSF, IL-4, IL-6, IL-8, IL-10, and oncostatin M did not change it. We examined for several autocrine loops that have been suggested to occur in KS. Experiments using antisense oligonucleotides showed that the clonal growth of KS-1 and BC-1 was nearly 100% inhibited by IL-6 antisense oligonucleotides (10 micromol/L), but not at all by either oligonucleotides (</=10 micromol/L) to IL-6 sense, IL-6 scrambled, viral IL-6 (vIL-6) antisense, or IL-10 antisense. Furthermore, the IL-6 antisense oligonucleotides had no effect on two B-cell lymphoma cell lines, which were not infected with KSHV. Addition of IL-6 antibody did not inhibit clonal growth of any of the cell lines. Taken together, we have defined the cytokines and their receptors expressed on PEL cells and have found that these cells synthesized IL-6 and IL-6 receptors; interruption of this pathway by IL-6 antisense oligonucleotides specifically prevented the growth of these cells. These findings will offer potential new therapeutic strategies for PEL.
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PMID:Mechanisms of growth control of Kaposi's sarcoma-associated herpes virus-associated primary effusion lymphoma cells. 951 48

Mast cell hyperplasia is often observed in dermatoses characterized by fibrosis. Evidence has accumulated showing that a potent fibrogenic cytokine, platelet-derived growth factor (PDGF), plays a pathogenic role in dermal fibrosis. To clarify the mechanism of mast cell hyperplasia associated with fibrosis, we investigated the effect of PDGF on mast cell proliferation and the expression of stem cell factor (SCF), a potent growth factor for mast cells, in fibroblasts. When mouse bone marrow-derived mast cells (BMMC) were cultured on a NIH/3T3 fibroblast monolayer, mast cell proliferation was stimulated in both cell number and total histamine content by all isoforms of PDGF (-AA, -AB, and -BB); however, none of the isoforms had any effect on [3H] thymidine incorporation in BMMC in the absence of fibroblasts. The effect of PDGF-AB and -BB were abrogated either by the addition of anti-PDGF-AB antibody or by the separation of mast cells and fibroblasts by a permeable membrane filter with a pore size of 0.2 microm. Immunoblotting of the NIH/3T3 fibroblasts treated with PDGF revealed an enhanced expression of SCF in the membrane fraction and the effect of PDGF was neutralized by the addition of antibody against SCF. Moreover, no effect of PDGF was observed when BMMC were prepared from W/W(v) mice that lack functional c-kit as the SCF receptor or when 3T3 fibroblasts were prepared from Sl/Sl(d) mice that lack membrane-bound SCF. These results suggest that the fibrogenic cytokine PDGF stimulates mast cell hyperplasia via the expression of membrane-bound SCF by fibroblasts in association with fibrosis of the skin.
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PMID:A fibrogenic cytokine, platelet-derived growth factor (PDGF), enhances mast cell growth indirectly via a SCF- and fibroblast-dependent pathway. 969 19

We have previously shown that fibroblast and keratinocyte supernatants up-regulate expression of mast cell characteristics in the human immature mast cell line HMC-1. This effect could not be induced in HMC-1 cells by the well-known mast cell growth factor stem cell factor (SCF), probably due to mutations of the SCF receptor c-Kit in these cells. Here we report the effects of several known fibroblast- and keratinocyte-derived growth factors, namely nerve growth factor (NGF), basic fibroblast growth factor, platelet-derived growth factor and transforming growth factor-beta, on mast cell differentiation, using HMC-1 cells as a model. NGF, at 0.1-50 ng/ml concentrations, caused a marked, dose-dependent up-regulation of tryptase, Fc epsilon RI and histamine within 10 days of culture, associated with an enhanced expression of mRNA for Fc epsilon RI and mast cell tryptase. On restriction analysis, only mast cell beta-tryptase, but not alpha-tryptase, could be demonstrated. Furthermore, the high-affinity NGF receptor (TrkA) was found at both the transcriptional and protein levels, while expression of the low-affinity NGF receptor was detectable at the mRNA level only. None of the other growth factors caused a significant alteration of the mast cell markers studied when added to HMC-1 cells at concentrations known to be biologically active in other culture systems. Immature human mast cells are thus induced to assume a more mature phenotype in vitro in response to NGF, most probably via stimulation of the high-affinity NGF receptor expressed on these cells. Besides SCF, NGF should therefore be considered as an additional mast cell growth factor that contributes to human mast cell maturation at tissue sites.
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PMID:Effects of nerve growth factor (NGF) and other fibroblast-derived growth factors on immature human mast cells (HMC-1). 977 35

Intestinal subepithelial myofibroblasts (ISEMF) and the interstitial cells of Cajal are the two types of myofibroblasts identified in the intestine. Intestinal myofibroblasts are activated and proliferate in response to various growth factors, particularly the platelet-derived growth factor (PDGF) family, which includes PDGF-BB and stem cell factor (SCF), through expression of PDGF receptors and the SCF receptor c-kit. ISEMF have been shown to play important roles in the organogenesis of the intestine, and growth factors and cytokines secreted by these cells promote epithelial restitution and proliferation, i.e., wound repair. Their role in the fibrosis of Crohn's disease and collagenous colitis is being investigated. Through cyclooxygenase (COX)-1 and COX-2 activation, ISEMF augment intestinal ion secretion in response to certain secretagogues. By forming a subepithelial barrier to Na(+) diffusion, they create a hypertonic compartment that may account for the ability of the gut to transport fluid against an adverse osmotic gradient. Through the paracrine secretion of prostaglandins and growth factors (e.g., transforming growth factor-beta), ISEMF may play a role in colonic tumorigenesis and metastasis. COX-2 in polyp ISEMF may be a target for nonsteroidal anti-inflammatory drugs (NSAIDs), which would account for the regression of the neoplasms in familial adenomatous polyposis and the preventive effect of NSAIDs in the development of sporadic colon neoplasms. More investigation is needed to clarify the functions of these pleiotropic cells.
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PMID:Myofibroblasts. II. Intestinal subepithelial myofibroblasts. 1044 94

PTK787/ZK 222584 (1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succinate) is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, such as the platelet-derived growth factor (PDGF) receptor beta tyrosine kinase, c-Kit, and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families, such as epidermal growth factor receptor, fibroblast growth factor receptor-1, c-Met, and Tie-2, or intracellular kinases such as c-Src, c-Abl, and protein kinase C-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of kinase insert domain-containing receptor (KDR), endothelial cell proliferation, migration, and survival in the nanomolar range in cell-based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once-daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown s.c. in nude mice, as well as a murine renal carcinoma and its metastases in a syngeneic, orthotopic model. Histological examination of tumors revealed inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent or impair hematopoetic recovery after concomitant cytotoxic anti-cancer agent challenge. This novel compound has therapeutic potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.
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PMID:PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. 1078 82

The staurosporine derivative PKC412 was originally identified as an inhibitor of protein kinase C (PKC) and subsequently shown to inhibit other kinases including the kinase insert domain receptor (KDR) (vascular endothelial growth factor receptor, VEGF-R2), the receptor of platelet-derived growth factor, and the receptor for the stem cell factor, c-kit. PKC412 showed a broad antiproliferative activity against various tumor and normal cell lines in vitro, and was able to reverse the Pgp-mediated multidrug resistance of tumor cells in vitro. Exposure of cells to PKC412 resulted in a dose-dependent increase in the G2/M phase of the cell cycle concomitant with increased polyploidy, apoptosis and enhanced sensitivity to ionizing radiation. PKC412 displayed a potent antitumor activity as single agent and was able to potentiate the antitumor activity of some of the clinically used cytotoxins (Taxol and doxorubicin) in vivo. The combined treatment of PKC412 with loco-regional ionizing irradiation showed significant antitumor activity against tumors which are resistant to both ionizing radiation and chemotherapeutic agents (dysfunctional p53). The finding that PKC412 is an inhibitor of the VEGF-mediated cellular signaling via inhibition of KDR and PKC in vitro is consistent with the in vivo inhibition of VEGF-dependent angiogenesis in a growth factor implant model. Orally administered PKC412 also strongly inhibited retinal neovascularization as well as laser-induced choroidal neovascularization in murine models. In summary, PKC412 may suppress tumor growth by inhibiting tumor angiogenesis in addition to directly-inhibiting tumor cell proliferation via its effects on PKC and/or other protein kinases. PKC412 is currently in Phase I clinical trials for treatment of advanced cancer as well as for the treatment of ischemic retinopathy.
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PMID:PKC412--a protein kinase inhibitor with a broad therapeutic potential. 1088 33

STI571 (formerly known as CGP 57148B) is a protein-tyrosine kinase inhibitor that is currently in clinical trials for the treatment of chronic myelogenous leukemia. STI571 selectively inhibits the Abl and platelet-derived growth factor (PDGF) receptor tyrosine kinases in vitro and blocks cellular proliferation and tumor growth of Bcr-abl- or v-abl-expressing cells. We have further investigated the profile of STI571 against related receptor tyrosine kinases. STI571 was found to potently inhibit the kinase activity of the alpha- and beta-PDGF receptors and the receptor for stem cell factor, but not the closely related c-Fms, Flt-3, Kdr, Flt-1, and Tek tyrosine kinases. Additionally, no inhibition of c-Met or nonreceptor tyrosine kinases such as Src and Jak-2 has been observed. In cell-based assays, STI571 selectively inhibited PDGF and stem cell factor-mediated cellular signaling, including ligand-stimulated receptor autophosphorylation, inositol phosphate formation, and mitogen-activated protein kinase activation and proliferation. These results expand the profile of STI571 and suggest that in addition to chronic myelogenous leukemia, STI571 may have clinical potential in the treatment of diseases that involve abnormal activation of c-Kit or PDGF receptor tyrosine kinases.
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PMID:Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. 1099 71

The 2-phenylaminopyrimidine derivative STI571 is a selective inhibitor of c-Abl, c-kit, and platelet-derived growth factor-receptor tyrosine kinases and is presently in phase II-III clinical studies. Here, this study reports on a novel pharmacologic activity of the compound, ie, enhancement of the cyto-differentiating, growth-inhibitory, and apoptogenic actions of all-trans-retinoic acid (ATRA). Whereas STI571 is not a cytodifferentiating agent by itself, the compound interacts with ATRA and enhances the myeloid maturation program set in motion by the retinoid in the PML-RARalpha(+) acute promyelocytic leukemia NB4 and the PML-RARalpha(-) myeloblastic HL60 and U937 cell lines. In addition, STI571 relieves the cyto-differentiation block observed in the ATRA-resistant cell lines, NB4.R1, NB4.306, and NB4.007. In NB4 promyelocytes, a RARalpha agonist, but not an RXR agonist, can substitute for ATRA and interact with STI571. By contrast, STI571 is unique among c-Abl-specific tyrosine kinase inhibitors in modulating the pharmacologic activity of ATRA. In NB4 cells, enhanced cyto-differentiation results in increased up-regulation of the expression of a number of genes coding for myeloid differentiation markers, including CD11b, CD11c, and some of the components of the nicotinamide adenine dinucleotide phosphate-oxidase enzymatic complex. All this is accompanied by inhibition of c-Abl tyrosine phosphorylation and retardation of the retinoid-dependent degradation of PML-RARalpha and RARalpha. Stabilization of the 2 retinoic acid receptors is likely to be the result of augmented and accelerated inhibition of the proteasome-dependent proteolytic activity observed on ATRA treatment.
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PMID:Tyrosine kinase inhibitor STI571 potentiates the pharmacologic activity of retinoic acid in acute promyelocytic leukemia cells: effects on the degradation of RARalpha and PML-RARalpha. 1134 54


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