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 (STI571, Gleevec, Glivec, a selective inhibitor of the BCR-ABL tyrosine kinase causative of chronic myeloid leukemia (CML), represents the paradigm of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a targeted molecular therapy. Phase II clinical trials have shown marked therapeutic activity of imatinib in all evolutive phases of CML, but notably in the chronic phase, where it induces complete hematological responses in almost 100% of patients resistant or intolerant to interferon, with a major cytogenetic response rate of 60%, including 41% complete cytogenetic responses. The preliminary results of an ongoing phase III multicenter randomized study comparing imatinib with interferon plus cytarabine as first-line treatment for CML favor imatinib in terms of efficacy and safety. If confirmed with longer follow-up,these results would establish imatinib as the choice therapy for the majority of CML patients, with allogeneic transplantation being restricted as initial therapy only to younger patients with a family donor. Longer follow-up will answer some questions, such as those on long-term safety, durability of the responses, whether these will translate into a survival prolongation and the possibility of molecular responses. In addition, further information on the mechanisms involved in the primary and acquired resistance to imatinib is needed. Besides the Bcr-Abl protein, the drug is also active against other tyrosine kinases, such as Abl, the stem-cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this sense, it must be pointed out that imatinib has shown a remarkable activity in gastrointestinal stromal tumors.
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PMID:Imatinib mesylate (Gleevec, Glivec): a new therapy for chronic myeloid leukemia and other malignancies. 1258 48

This study characterizes 3 cases of mesenchymal chondrosarcoma (MC) utilizing a proteomic approach that allows for the detection, visual quantification, cellular compartmentalization, and assessment of the functional state of certain proteins that may promote tumor growth and/or oppose apoptosis. Immunohistochemical procedures were performed to detect the following protein antigens: CD99, interleukin (IL)-1alpha, IL-6, transforming growth factor (TGF)-alpha, conventional (c) protein kinase C (cPKC)-alpha, cPKC-betaII, phosphorylated (p)-PKC-alpha/betaII, c-kit (CD117), platelet-derived growth factor receptor (PDGFR)-alpha, PDGFR-beta, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)-2/neu, cathepsin D, angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) receptor, p21ras, the alpha subunit of farnesyl and geranylgeranyl transferase (FTalpha/GGTalpha), phospho (p)-c-Jun N-terminal kinase (p-JNK), p-p38 mitogen-activated protein kinase (MAPK), cyclin D1, c-Jun, Ki-67, bcl-2, TGF-beta1 latency-associated peptide (LAP), TGF-betaRII, and cyclooxygenase (COX)-2. Immunoreactivities were scored from 0 to 3+ positivity using bright-field microscopy. The results showed that malignant mesenchymal chondroblasts exhibit stronger expressions of CD99, IL-1alpha, cPKC-alpha, p-PKC-alpha/betaII, PDGFR-alpha, p-JNK, Ki-67, and bcl-2 antigens than their more mature-appearing chondrocytic counterparts in MC. In conclusion, molecular profiling of mesenchymal chondrosarcoma using a proteomic approach characterized the mesenchymal chondroblasts as possessing pathways that incorporate PKC-alpha and PDGFR-alpha signaling and anti-apoptotic bcl-2 expression. Specific therapies to target the mesenchymal chondroblasts in mesenchymal chondrosarcoma might include interferon-alpha, rapamycin, ciprofloxacin, and STI571.
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PMID:Mesenchymal chondrosarcoma: molecular characterization by a proteomic approach, with morphogenic and therapeutic implications. 1281 16

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

STI571 is a 2-phenylaminopyrimide derivative that was designed as an Abl tyrosine kinase inhibitor, but it is also effective against platelet-derived growth factor receptor (PDGFR) and c-Kit tyrosine kinase. Recent studies have demonstrated that STI571 inhibits the growth of several tumors in which PDGF or c-kit play an important role in tumor pathogenesis. We have recently established rat osteosarcoma and malignant fibrous histiocytoma (MFH) cell lines. RT-PCR analysis revealed that MFH and osteosarcoma cell lines expressed high and very low levels of PDGFR alpha respectively, and that all cell lines expressed similar levels of PDGFR beta. The level of c-kit mRNA expression were almost negligible hardly in all cell lines. The effect of STI571 on cellular growth measured by MTS colorimetric dye reduction showed that the growth of each cell line was inhibited in a dose- and time-dependent manner. STI571 (10 microM) inhibited the rates of cell growth of MFH cells by up to 40% and of osteosaroma cells by only to 20% after 72 hours. These data suggested that STI571 tyrosine kinase inhibitor plays a role in blocking or slowing the rate of growth of MFH and osteosarcoma cells expressing tyrosine kinase type receptor.
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PMID:Growth inhibition of rat osteosarcoma and malignant fibrous histiocytoma cells by tyrosine kinase inhibitor STI571. 1292 76

Imatinib mesylate is a 2-phenylaminopyrimidine tyrosine kinase inhibitor with specific activity for ABL, platelet-derived growth factor receptor, and c-kit receptor. The pharmacological basis of this interaction has been elucidated by crystallographic studies. Imatinib mesylate binds to the amino acids of the BCR-ABL tyrosine kinase ATP binding site and stabilizes the inactive, non-ATP-binding form of BCR-ABL, thereby preventing tyrosine autophosphorylation, and in turn, phosphorylation of its substrates. This process ultimately results in a "switch-off" of the downstream signaling pathways that promote leukemogenesis. Despite high rates of hematologic and cytogenetic responses to imatinib therapy, the emergence of resistance to imatinib has been recognized as a major problem in the treatment of Ph-positive leukemia. Considerable progress has been made in developing therapeutic agents that are effective against molecular targets specifically expressed in CML cells. It is important to emphasize that BCR-ABL is the ideal target for therapy even at relapse; at least one general mechanism of resistance involves maintenance of an active BCR-ABL kinase inside leukemic cells. It is also notable that the high frequency of BCR-ABL mutations and amplifications represents the high degree of heterogeneity in patients with advanced CML, in whom multiple leukemic clones may exist. For these reasons, a single inhibitor is unlikely to be able to block all mutants described so far.
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PMID:[Molecular-target therapy of Ph-positive leukemia by imatinib (tyrosine kinase inhibitor)]. 1293 59

The antileukaemic tyrosine kinase inhibitor, imatinib, has been reported to inhibit specifically the growth of bcr-abl expressing CML progenitors at levels of 0.1-5.0 microM, by blocking the ATP-binding site of the kinase domain of bcr-abl. Inhibition of the c-abl, platelet-derived growth factor receptor and stem cell factor receptor (c-kit) tyrosine kinases by imatinib has also been reported. Here, we demonstrate that imatinib significantly inhibits in vitro monocyte/macrophage development from normal bone marrow progenitors, while neutrophil and eosinophil development was less affected. Monocyte/macrophage inhibition was observed in semisolid agar and liquid cultures at concentrations of imatinib as low as 0.3 microM. The maturation of monocytes into macrophages was also found to be impaired following treatment of cultures with 1.0 microM imatinib. Imatinib blocked monocyte/macrophage development in cultures stimulated with and without M-CSF, suggesting that inhibition of the M-CSF receptor, c-fms, by imatinib was unlikely to be responsible. Imatinib may therefore have an inhibitory activity for other kinase(s) that play a role in monocyte/macrophage differentiation. This inhibition of normal monocyte/macrophage development was observed at concentrations of imatinib achievable pharmacologically, suggesting that imatinib or closely related derivatives may have potential for the treatment of diseases where monocytes/macrophages contribute to pathogenesis.
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PMID:Imatinib inhibits the in vitro development of the monocyte/macrophage lineage from normal human bone marrow progenitors. 1297 Jul 69

Imatinib mesylate (STI571) is a competitive Bcr-Abl tyrosine kinase inhibitor and has yielded encouraging results in treatment of chronic myelogenous leukemia (CML) and gastrointestinal stroma tumors (GISTs). Apart from inhibition of the Abl protein tyrosine kinases, it also shows activity against platelet-derived growth factor receptor (PDGF-R), c-Kit, Abl-related gene (ARG), and their fusion proteins while sparing other kinases. In vitro studies have revealed that imatinib mesylate can inhibit growth of cell lines and primitive malignant progenitor cells in CML expressing Bcr-Abl. However, little is known about the effects of imatinib mesylate on nonmalignant hematopoietic cells. In the current study we demonstrate that in vitro exposure of mobilized human CD34+ progenitors to therapeutic concentrations of imatinib mesylate (1-5 microM) inhibits their differentiation into dendritic cells (DCs). DCs obtained after 10 to 16 days of culture in the presence of imatinib mesylate showed concentration-dependent reduced expression levels of CD1a and costimulatory molecules such as CD80 and CD40. Furthermore, exposure to imatinib mesylate inhibited the induction of primary cytotoxic T-lymphocyte (CTL) responses. The inhibitory effects of imatinib mesylate were accompanied by down-regulation of nuclear localized RelB protein. Our results demonstrate that imatinib mesylate can act on normal hematopoietic cells and inhibits the differentiation and function of DCs, which is in part mediated via the nuclear factor kappaB signal transduction pathway.
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PMID:Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells. 1497 62

Neoplastic transformation is often related to abnormal activation of growth factor receptors and their signaling pathways. The concept of targeting specific tumorigenic receptors and/or signaling molecules has been validated by the development and successful clinical application of drugs acting against the epidermal growth factor receptor 2 (HER2/neu, Erb2), the epidermal growth factor receptor 1 (EGFR, HER1), the Brc-Abl kinase, the platelet-derived growth factor receptor, and c-kit. This review will focus on the next promising therapeutic target, the insulin-like growth factor I receptor (IGF-IR). IGF-IR has been implicated in a number of neoplastic diseases, including several common carcinomas. From a pharmaceutical standpoint, of particular importance is that IGF-IR appears to be required for many transforming agents (genetic, viral, chemical) to act, but is not obligatory for the function of normal adult cells. The tumorigenic potential of IGF-IR is mediated through its antiapoptotic and transforming signaling, and in some cases through induction of prometastatic pathways. Preclinical studies demonstrated that downregulation of IGF-IR reversed the neoplastic phenotype and sensitized cells to antitumor treatments. The strategies to block IGF-IR function employed anti-IGF-IR antibodies, small-molecule inhibitors of the IGF-IR tyrosine kinase, antisense oligodeoxynucleotides and antisense RNA, small inhibitory RNA, triple helix, dominant-negative mutants, and various compounds reducing ligand availability. The experience with these strategies combined with the knowledge gained with current anti-growth factor receptor drugs should streamline the development of anti-IGF-IR therapeutics.
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PMID:Growth factor receptors as therapeutic targets: strategies to inhibit the insulin-like growth factor I receptor. 1452 84

Growth, survival and differentiation of hematopoietic cells are regulated by the interaction between hematopoietic growth factors and their receptors. While the defect in this interaction results in an insufficient hematopoiesis, the aberrantly elevated activation leads to the transformation of hematopoietic cells. The constitutive active mutations of receptor tyrosine kinase, such as c-Kit platelet-derived growth factor receptor (PDGFR) or fins-like tyrosine kinase 3 (Flt3), play a major role in the development of hematopoietic neoplasia. The constitutive activation is provoked by several mechanisms, such as making fusion genes by chromosomal translocations, or various mutations involving regulatory regions of the receptor. The chromosomal translocation brings the receptor intracytoplasmic domain juxtaposed to an unrelated molecule which has dimerization or multimerization motif, resulting in the constitutive dimerization of the receptor. The missense, insertion or deletion mutations in the regulatory regions, such as juxtamembrane domain, activation loop and extracellular domain, cause constitutive activation by releasing the respective auto-inhibitory functions of each regulatory region. Constitutive active receptors generate different signals quantitatively and qualitatively from wild type receptor, which mediate the oncogenic phenotype. Given the frequent involvement of constitutive active receptor tyrosine kinase in hematopoietic malignancies, targeted inhibitions of active tyrosine kinase and downstream aberrant signaling are rapidly developing novel therapeutic modality with much promise.
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PMID:Oncogenic receptor tyrosine kinase in leukemia. 1465 48

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These tumors develop at any site but are most commonly reported in the stomach. They originate from the neoplastic transformation of the intestinal pacemaker cell, the interstitial cell of Cajal. GISTs strongly express the receptor tyrosine kinase KIT and have mutations in the KIT gene, most frequently in exon 11 encoding the intracellular juxtamembranous region. Expression of KIT is seen in almost all GISTs, regardless of the site of origin, histologic appearance, or biologic behavior, and is therefore regarded as one of the key diagnostic markers. Distinction from smooth muscle tumors, such as leiomyosarcomas, and other mesenchymal tumors is very important because of prognostic differences and therapeutic strategies. Predicting the biologic behavior of GISTs is often difficult by conventional pathologic examination; tumor size and mitotic rate are the most important prognostic indicators. The prognostic significance of KIT mutations is controversial and thus far has not been clearly linked with biologic behavior. KIT mutations are associated with tumor development, and cytogenetic aberrations are associated with tumor progression. The pathogenesis of GISTs involves a gain-of-function mutation in the KIT proto-oncogene, leading to ligand-independent constitutive activation of the KIT receptor. KIT-wild-type GISTs have shown mutually exclusive platelet-derived growth factor receptor (PDGFR) mutation and activation. The use of imatinib mesylate (also known as Gleevec or STI-571) has greatly increased the therapeutic efficacy for this otherwise chemotherapy-resistant tumor. GISTs with very low levels of KIT expression may respond to imatinib mesylate therapy if the receptors are activated by specific mechanisms. KIT-activating mutations fall into two groups: the regulatory type and the enzymatic site type. The regulatory type of mutation is conserved at the imatinib binding site, whereas the enzymatic site mutation has a structurally changed drug-binding site, resulting in drug resistance. Resistance to the drug is the major cause of treatment failure in cancer therapy, emphasizing the need for researchers to understand KIT signaling pathways so as to identify new therapeutic targets. This review summarizes the pathologic features of GISTs, recent advances in understanding their molecular and biologic features, and therapy with imatinib mesylate.
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PMID:Gastrointestinal stromal tumors: overview of pathologic features, molecular biology, and therapy with imatinib mesylate. 1502 16


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