Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The usefulness of phosphotyrosine antibodies for the detection of physiologically regulated or deregulated tyrosine kinases is discussed in this report. This rather rare enzymatic activity is shared by receptors for some polypeptide growth factors and by the products of Class 1 oncogenes. The antibodies are able to detect proteins phosphorylated on tyrosine in fibroblasts stimulated with growth factors such as EGF and PDGF. The major phosphorylated protein species are the receptors themselves, which undergo phosphorylation only after the addition of the exogenous factor and only transiently. Phosphotyrosine antibodies were able to detect the products of the retroviral Class 1 oncogenes, which are endowed with deregulated tyrosine kinase activity. In fact, in these cases a constitutive phosphorylation of the relevant proteins was observed, which occurred continuously and independently of the presence or lack of exogenous ligands. A tyrosine kinase constitutively activated in human gastric carcinoma cells was detected by P-Tyr antibodies. This molecule has been characterized at the molecular level, and the mechanisms responsible for its enzymatic activation have been investigated. The question of whether the tyrosine kinase identified is responsible for the induction and the maintenance of the transformed phenotype in gastric carcinomas remains to be answered. It is reasonable to suggest that this might be the case by analogy with other situations such as Class 1 oncogenes activated by transduction by retroviruses, abnormal expression of EGF receptors, or deregulated activity of c-abl-encoded proteins in chronic myelogenous leukemia and acute lymphoblastic leukemia. Thus, the search for deregulated kinases by means of phosphotyrosine antibodies seems to be useful for identifying new activated oncogenes in clinical oncology.
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PMID:Tyrosine kinase and control of cell proliferation. 170 Dec 90

The usefulness of phosphotyrosine antibodies for the detection of physiologically regulated or deregulated kinases is shown in this paper. This rather rare enzymatic activity is shared by receptors for some polypeptide growth factors and by the products of class 1 oncogenes. The antibodies are able to detect proteins phosphorylated on tyrosine in fibroblasts stimulated with growth factors, such as EGF and PDGF. The major phosphorylated protein species are the receptors themselves, which undergo phosphorylation only following the addition of the exogenous factor and only transiently. Phosphotyrosine antibodies were able to detect the products of the retroviral class 1 oncogenes, which are endowed of deregulated tyrosine kinase activity. In fact, in these cases a constitutive phosphorylation of the relevant proteins was observed, which occurred continuously and independently of the presence or lack of the growth factor. A tyrosine kinase constitutively activated in human gastric carcinoma cells was detected by P-Tyr antibodies. This molecule has been characterized at molecular level and the mechanisms responsible for its enzymatic activation has been investigated. The question of whether the tyrosine kinase identified is responsible for the induction and the maintenance of the transformed phenotype in gastric carcinomas remains to be answered. It is reasonable to suggest that this might be the case by analogy with other known pathologies, such as class 1 oncogenes activated by transduction by retroviruses, abnormal expression of EGF receptors or deregulated activity of c-abl encoded proteins in CML and ALL. Thus, the search for deregulated kinases by means of phosphotyrosine antibodies seems to be useful for identifying new activated oncogenes in clinical oncology.
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PMID:Phosphotyrosine antibodies as probes for activated oncogene products endowed with tyrosine kinase activity. 172 Feb 92

axl is a transforming receptor tyrosine kinase isolated from DNA of patients with chronic myelogenous leukemia. Association of axl expression with myelogenous leukemias and its expression in primitive hematopoietic cells suggests a role for axl in myeloid biology. To study the cellular function of axl, we constructed a chimeric receptor tyrosine kinase composed of the extracellular and transmembrane domains of the EGF receptor and the cytoplasmic domain of axl; this chimera was named EAK for EGFR-Axl-Kinase. The EAK chimeric receptor was expressed in the mouse myeloid progenitor cell line 32D, which is dependent on interleukin 3 (IL-3) for proliferation and survival. Treatment of the 32D-EAK cells with EGF stimulated the tyrosine phosphorylation of the axl kinase domain and enabled proliferation through EGF rather than IL-3. Thus, axl can effectively couple with mitogenic signaling pathways intrinsic to 32D myeloid cells. Assay of proteins phosphorylated in response to different cytokine treatments showed that IL-3 and EGF exposure produced unique profiles in the 32D-EAK cells. Furthermore, Jak-2 is phosphorylated only in response to IL-3 treatment in these cells. This suggests that IL-3 receptor and axl transduce mitogenic signals through separate pathways. In addition, exposure of cells expressing the chimeric receptor to EGF for 19 days converted the cells to factor-independent growth, a phenomenon not seen with other receptor tyrosine kinases. Generation of this transformed phenotype is absolutely dependent on axl activation by foster ligand. The tyrosine phosphorylation level of the axl kinase domain in the factor-independent subclones is 40-fold greater than the factor-dependent cells. The association of a unique axl phosphorylation level with the factor-independent phenotype suggests that there is a threshold phosphorylation level of the axl kinase for transformation. The fact that activation of the axl receptor leads to transformation of 32D cells suggests that axl can play a role in leukemic conversion of myeloid cells, either through inappropriate expression or improper activation.
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PMID:Activation of the Axl receptor tyrosine kinase induces mitogenesis and transformation in 32D cells. 784 12

The urinary concentration of calmodulin and basic fibroblast growth factor (bFGF) was determined in a total of 53 patients with various chronic myeloproliferative disorders (CMPD), including 22 patients with idiopathic myelofibrosis (IMF). Calmodulin excretion was significantly elevated in IMF (0.29 +/- 0.04 microgram/mmol creatinine) (P < 0.001), when compared to polycythaemia vera (PV) (0.14 +/- 0.02), essential thrombocythaemia (ET) (0.13 +/- 0.04), chronic myeloid leukaemia (CML) (0.16 +/- 0.02), unclassified myeloproliferative disorders (UMPD) (0.11 +/- 0.02) and age-matched controls (0.1 +/- 0.02) (P < 0.001). In contrast, bFGF was slightly elevated in all CMPD conditions when compared to age-matched controls. A neutralizing antibody to calmodulin was demonstrated to significantly influence the in vitro proliferation of normal human fibroblasts, an effect dependent on both cell density and the presence of fetal calf serum (FCS). Essentially, the antibody reduced FCS-induced proliferation of low-density fibroblasts but had little or no inhibitory effect on high-density fibroblasts in the absence of FCS. In addition, extracellular calmodulin was shown not to interact with known fibroblast mitogens, namely, IFG-1, EGF, bDGF and PDGF. We conclude that extracellular calmodulin should be considered, in addition to PDGF, TFG-beta and EGF, as a potential mitogen involved in the stromal reaction of idiopathic myelofibrosis.
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PMID:Investigation of calmodulin and basic fibroblast growth factor (bFGF) in idiopathic myelofibrosis: evidence for a role of extracellular calmodulin in fibroblast proliferation. 870 17

Protein kinases play a crucial role in signal transduction as well as in cellular proliferation, differentiation, and various regulatory mechanisms. The inhibition of growth related kinases, especially tyrosine kinases, might provide new therapies for diseases such as cancer. The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design. Three successful examples of drug design at Novartis using a tyrosine kinase as a molecular target are described. PKI166, a pyrrolo[2,3,-d]pyrimidine derivative, is a dual inhibitor of both the EGFR and the ErbB2 kinases. The compound entered clinical trials in 1999, based on its favorable preclinical profile: potent inhibition of EGF-mediated signalling in cells, in vivo antitumor activity in several EGFR overexpressing xenograft tumor models in nude mice, long-lasting inhibition of EGF-stimulated EGFR autophosphorylation in tumor tissue, good oral bioavailability in animals, and no prohibitive in vitro and in vivo toxicity findings. The anilino-phthalazine derivative PTK787/ZK222584 (Phase I, co-developed by Schering AG, Berlin) is a potent and selective inhibitor of both the KDR and Flt-1 kinases with interesting anti-angiogenic and pharmacokinetic properties (orally bioavailable). STI571 (Glivec, Gleevec), a phenylamino-pyrimidine derivative, is a potent inhibitor of the Abl tyrosine kinase, which is present in 95% of patients with chronic myelogenous leukemia (CML). The compound specifically inhibits proliferation of v-Abl and Bcr-Abl expressing cells (including cells from CML patients) and shows anti-tumor activity as a single agent in animal models at well-tolerated doses. Pharmacologically relevant concentrations are achieved in the plasma of animals (oral administration). Promising data from phase I and II clinical trials in CML patients (98% haematological response rate in Phase I) support the fact that the STI571 represents a new treatment modality for CML. In addition, potent inhibition of the PDGFR and c-Kit tyrosine kinases also indicates its possible clinical use in solid tumors.
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PMID:Tyrosine kinase inhibitors: from rational design to clinical trials. 1160 31

Cellular receptors for the Epidermal Growth Factor (EGF-R) are members of the ErbB receptor family and are considered important targets for the experimental treatment of human cancer. Monoclonal antibodies as well as small tyrosine kinase inhibitors (TKIs) have been developed and have undergone extensive evaluation in preclinical and clinical studies based on the general idea that EGF-R plays a critical role on the growth and survival of human tumors. This assumption has been derived by the successful development of BCR/ABL tyrosine kinase inhibitors in human chronic myeloid leukemia as well as on the activity of therapy with monoclonal antibodies (mAb) in breast cancer and lymphoproliferative diseases. It is now becoming clear that factors regulating sensitivity to kinase inhibitors may differ from monoclonal antibodies and that the molecules targeted by interfering drugs must be prioritaire for growth and survival of those specific tumors in order to achieve valuable results. In this article, we will describe the signal transduction pathways regulated by EGF-R and the principal pharmacological and biotechnological agents directed against EGF-R. We will discuss the significance of targeting the EGF-R driven survival pathways and the compensatory intracellular survival mechanisms that counteract the specific EGF-R inhibition and are the cause of the poor clinical results derived from study based on the use of these agents. We will describe new multipotent TKIs that target also other members of ErbB family (i.e. ErbB2) blocking one of the compensatory mechanism that can be triggered in cancer cells. Moreover, we will report new patent on bispecific mAbs that bind EGF-R and immune effectors in order to increase the immunological function of this agent that could be the basis of the different clinical results achieved with the use of TKI and mAbs. Finally, we will propose a pharmacological model able to make cancer cells dependent on EGF-R for their survival and proliferation and we will discuss the relevance of patenting also new therapeutical strategies and not only the simple drug.
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PMID:EGF-R small inhibitors and anti-EGF-R antibodies: advantages and limits of a new avenue in anticancer therapy. 1822 Oct 38

Targeted therapies have made their way into clinical practice during the past decade. They have caused a major impact on the survival of cancer patients in many areas of clinical oncology and hematology. Indeed, in some hematologic malignancies, such as chronic myelogenous leukemia or non-Hodgkin's lymphomas, biologicals and antibodies specifically designed to target tumour-specific proteins have revolutionized treatment standards. In solid tumours, new drugs targeting EGF- or VEGF- receptors are now approved and are entering clinical practise for treatment of colon, lung, kidney and other cancers, either alone or in combination with conventional treatment approaches. Recent data have now shown that molecular targeted therapy might display efficacy in patients with head and neck squamous cell carcinoma (HNSCC) as well. The evaluated biologicals are generally well tolerated from HNSCC patients, who usually have the burden of multiple co-morbidities that interfere with conventional systemic treatment options. Therefore, molecular targeted therapies offer new treatment options even for heavily pretreated and seriously ill patients usually unable to tolerate chemotherapy or radiation therapy. The two most promising and advanced strategies are the blockage of growth-factor based cellular signalling and interference with angiogenesis-related pathways. But inhibitors of alternative targets, such as Scr and proteasomes, have already been evaluated in early clinical trials with HNSCC patients.
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PMID:Molecular targeted therapies in head and neck cancer--an update of recent developments-. 2039 56

The use of selective inhibitors targeting Bcr-Abl kinase is now established as a standard protocol in the treatment of chronic myelogenous leukemia; however, the acquisition of drug resistance is a major obstacle limiting the treatment efficacy. To elucidate the molecular mechanism of drug resistance, we established K562 cell line models resistant to nilotinib and imatinib. Microarray-based transcriptome profiling of resistant cells revealed that nilotinib- and imatinib-resistant cells showed the upregulation of kinase-encoding genes (AURKC, FYN, SYK, BTK and YES1). Among them, the upregulation of AURKC and FYN was observed both in nilotinib- and imatinib-resistant cells irrespective of exposure doses, while SYK, BTK and YES1 showed dose-dependent upregulation of expression. Upregulation of EGF and JAG1 oncogenes as well as genes encoding ATP-dependent drug efflux pump proteins such as ABCB1 was also observed in the resistant cells, which may confer alternative survival benefits. Functional gene set analysis revealed that molecular categories of 'ATPase activity', 'cell adhesion' or 'tyrosine kinase activity' were commonly activated in the resistant clones. Taken together, the transcriptome analysis of tyrosine kinase inhibitors (TKI)-resistant clones provides the insights into the mechanism of drug resistance, which can facilitate the development of an effective screening method as well as therapeutic intervention to deal with TKI resistance.
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PMID:Gene expression signatures associated with the in vitro resistance to two tyrosine kinase inhibitors, nilotinib and imatinib. 2282 91

Eupolyphaga sinensis Walker is not only used as a food to enhance immunity, but is used as a traditional Chinese medicine and is known as the "preferred drug to regulate blood flow". Previous studies have reported its potential biological activities including anticoagulation, antithrombotic, liver protective effect and antitumor effects. Our results indicated that E. sinensis Walker 70% ethanol extract exhibited anti-tumor effects on S180 (murine sarcoma cell line) cells implanted mice. It effectively inhibited K562 (human chronic myeloid leukemia cell line) cells proliferation and induced G(2)-M phase arrest accompanying through up-regulation of cyclin B1, cdc2 and down-regulation of cyclin D1, cyclin E1, cdc25c and p53. In addition, it inhibited EGF secretion and EGFR kinase activity. Western blotting analysis indicated that it also inhibited the phosphorylation EGFR and activation of its downstream signaling molecules AKT and ERK. These results suggested that the antitumor mechanism of E. sinensis Walker involved altering the cell cycle and inhibiting EGFR phosphorylation in the EGFR signaling pathway.
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PMID:Eupolyphaga sinensis Walker inhibits human chronic myeloid leukemia cell K562 growth by inducing G2-M phase cell cycle arrest and targeting EGFR signaling pathway and in S180 tumor-bearing mice. 2481 61

The non-receptor tyrosine kinase ABL drives myeloid progenitor expansion in human chronic myeloid leukemia. ABL inhibition by the tyrosine kinase inhibitor nilotinib is a first-line treatment for this disease. Recently, ABL has also been implicated in the transforming properties of solid tumors, including triple negative (TN) breast cancer. TN breast cancers are highly metastatic and several cell lines derived from these tumors display high invasive activity in vitro. This feature is associated with the activation of actin-rich membrane structures called invadopodia that promote extracellular matrix degradation. Here, we investigated nilotinib effect on the invasive and migratory properties of different TN breast cancer cell lines. Nilotinib decreased both matrix degradation and invasion in the TN breast cancer cell lines MDA-MB 231 and MDA-MB 468. However, and unexpectedly, nilotinib increased by two-fold the invasive properties of the TN breast cancer cell line BT-549 and of Src-transformed fibroblasts. Both display much higher levels of ABL kinase activity compared to MDA-MB 231. Similar effects were obtained by siRNA-mediated down-regulation of ABL expression, confirming ABL central role in this process. ABL anti-tumor effect in BT-549 cells and Src-transformed fibroblasts was not dependent on EGF secretion, as recently reported in neck and squamous carcinoma cells. Rather, we identified the TRIO-RAC1 axis as an important downstream element of ABL activity in these cancer cells. In conclusion, the observation that TN breast cancer cell lines respond differently to ABL inhibitors could have implications for future therapies.
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PMID:ABL tyrosine kinase inhibition variable effects on the invasive properties of different triple negative breast cancer cell lines. 2580 21


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