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)

Several studies have emphasized the significance of neoangiogenesis for tumor growth and progression, but few have focused on malignant hematological disorders. We studied vascular density and architecture in bone marrow samples of patients with chronic myeloproliferative disease (MPD). Vascular structures were immunostained (for von Willebrand factor/FVIII-RAG, CD 31/PECAM or Ulex europeus I for vessels and for vascular endothelial growth factor, VEGF) in samples from patients with polycythemia vera (PV) (n = 7), chronic myelocytic leukemia (CML) (n = 9), and myelofibrosis (MF) (n = 6) when diagnosed and were compared with normal bone marrow specimens (n = 9). We observed that the mean (+/- SD) vessel count per high-power microscopy field (HPF) was 5.3 (+/- 2.1) in normal bone marrow, 5.9 (+/- 2.1) in PV, 10.8 (+/- 3.2) in CML, and 14.4 (+/- 5.5) in MF (P < 0.001 for CMP and MF versus controls). Confocal microscopy, including three-dimensional reconstructions of the blood vessel architecture, confirmed this increased vessel density and revealed tortuous vessel architecture and increased branching in the MPD, particularly in CML and MF. Furthermore, the number of VEGF-positive bone marrow cells was increased in CML and, particularly, in MF. Numbers of VEGF-positive cells and vessels per HPF correlated significantly (r = 0.41; P = 0. 037). Thus the myeloproliferative diseases PV, CML, and MF exhibit neoangiogenesis that is related to diagnosis.
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PMID:Bone marrow in polycythemia vera, chronic myelocytic leukemia, and myelofibrosis has an increased vascularity. 1088 Mar 70

To further elucidate the role of angiogenesis in the pathogenesis of chronic myelogenous leukemia (CML) we evaluated the effects of the bcr-abl translocation on the secretion of the angiogenic factors VEGF, FGF-2, HGF, IL-8 and matrix metalloproteinases (MMPs) as well as on the angiogenic potential in vivo of bcr-abl+ cells. First, we examined murine FL5.12 cells transfected with the bcr-abl constructs p185, p210 and p230 and found that the transfected cells secreted as much as four-fold more VEGF (p185 > p210 >p230) than wild-type (wt) cells, as well as MMP-9 and MMP-2. When Matrigel fragments containing these bcr-abl+ cells were implanted subcutaneously in SCID or Balb-C mice they became significantly more vascularized and hemoglobinized than implants containing normal or wt cells (p185 > p210 > p230). Similarly, we found that myeloblasts expanded from bone marrow (BM) CD34+ cells derived from Philadelphia-positive CML patients secreted up to 10 times more VEGF, FGF-2, HGF and IL-8 compared to myeloblasts derived from normal donors' BM CD34+ cells and that BM mononuclear cells (MNC) isolated from CML patients induced vascularization of Matrigel implants in mice. Moreover, we found that peripheral blood MNC expressed MMP-2 and membrane-type (MT)1-MMP in about 50% of CML patients studied, and MMP-9 in all of them. Furthermore, VEGF stimulated the secretion of MMP-9 in these primary CML cells. We conclude that stimulation of angiogenesis by angiogenic factors, including MMPs, could play an important role in the pathogenesis of CML, suggesting that therapies targeting the newly formed endothelium could be developed for CML.
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PMID:Bcr-abl-positive cells secrete angiogenic factors including matrix metalloproteinases and stimulate angiogenesis in vivo in Matrigel implants. 1204 Apr 48

Deregulation of protein kinase activity has been shown to play a central role in the pathogenesis of human cancer. The molecular pathogenesis of chronic myelogenous leukemia (CML) in particular, depends on formation of the bcr-abl oncogene, leading to constitutive expression of the tyrosine kinase fusion protein, Bcr-Abl. Based on these observations, imatinib was developed as a specific inhibitor for the Bcr-Abl protein tyrosine kinase. The expanding understanding of the basis of imatinib-mediated tyrosine kinase inhibition has revealed a spectrum of potential new antitumor applications beyond the powerful activity already reported in the treatment of CML. Imatinib has shown activity in vivo against PDGF-driven tumor models including glioblastoma, dermatofibrosarcoma protuberans and chronic myelomonocytic leukemia. Antiangiogenic effects have been demonstrated by inhibition of PDGF-, VEGF (vascular endothelial growth factor)- and bFGF- (basic fibroblast growth factor) induced angiogenesis in vivo, and by inhibition of angiogenesis and tumor growth in an experimental bone metastasis model. Imatinib has been shown to reduce interstitial fluid pressure in an experimental colonic carcinoma model by blocking PDGF-mediated effects on tumor-associated blood vessels and stromal tissue. It is also a potent inhibitor of the Kit receptor tyrosine kinase, and has demonstrated activity clinically against the Kit-driven gastrointestinal stromal tumor (GIST) and experimentally in small-cell lung cancer cell lines. The pharmacology of imatinib and its activity in various tumor models is discussed.
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PMID:Pharmacology of imatinib (STI571). 1252 70

Glucose can react non-enzymatically with amino groups of, for example, proteins, to yield derivatives termed advanced glycation end products (AGE), which contribute to many chronic progressive diseases associated with microvascular complications. The study aimed to determine the effect of AGE-modified albumin on THP-1 cells and human monocyte-derived macrophages. Bovine serum albumin (BSA) or human serum albumin (HSA), modified by glucose-derived AGE, was prepared by incubation with glucose for differing periods of time. Alternatively, BSA was incubated with sodium cyanoborohydride and glyoxylic acid to produce N(epsilon)-(carboxymethyl)lysine-modified BSA (CML-BSA). Stimulation for 24h of THP-1 cells with BSA, incubated for 6-8 weeks with glucose, induced significant VEGF release. Human monocyte-derived macrophages stimulated with extensively glycated HSA also showed significant VEGF release, as well as upregulation of IL-8 production, incubation for 6h with extensively glycated HSA increased release of TNFalpha and expression of tissue factor. Finally, addition of CML-BSA resulted in significant induction of TNFalpha and VEGF release. We demonstrate that a range of different methods of glycation of BSA and HSA, including CML-BSA, resulted in the induction of VEGF, TNFalpha, IL-8 and expression of tissue factor, according to length of stimulation and different glycation products used, suggesting that AGE-induced activation of macrophages may contribute to vascular complications by regulation of angiogenic, inflammatory and pro-coagulant processes.
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PMID:Advanced glycation end products upregulate angiogenic and pro-inflammatory cytokine production in human monocyte/macrophages. 1534 24

An antisense strategy by targeting both bcr3/abl2 and VEGF was designed to suppress the growth of Philadephia1 leukemia cells in vitro and in vivo in mice. In vitro, although bcr3/abl2 or VEGF antisense oligodeoxyribonucleotides (AS-ODNs) alone was able to inhibit the proliferation of K562 cells, the combination of bcr3/abl2 and VEGF AS-ODNs produced an additive inhibitory effect on the growth of K562 cells and significantly enhanced the sensibility of K562 cells to apoptosis-inducing stimuli including STI571. In vivo, the nude mice xenografted with K562 cells received intratumoral injections of bcr3/abl2 and VEGF AS-ODNs showed a significant reduction in leukemia tumor size and microvessel density and an increase of apoptosis in the tumors when compared to the mice that received an individual agent. These results demonstrate that targeting both bcr3/abl2 and VEGF can result in an additive tumor-suppressive action and may represent an excellent strategy to augment the efficacy of chemotherapy in CML.
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PMID:Enhanced growth suppression of Philadephia1 leukemia cells by targeting bcr3/abl2 and VEGF through antisense strategy. 1603 68

Recent investigations support the idea that angiogenesis is involved in the pathophysiology of hematologic malignancies, including chronic myeloid leukemia (CML). The aim of the present study was to evaluate plasma levels of VEGF and bFGF in a cohort of 51 chronic-phase CML patients at the time of diagnosis, as well as to investigate the effect of imatinib therapy on VEGF amounts in CML patients. Plasma VEGF levels were significantly higher in patients studied as compared with the 20 healthy subjects (p<0.001), the median plasma VEGF level detected in patients analysed and healthy controls was 433.4 pg mL(-1) (range 65.2-2,452.7 pg mL(-1)) and 81.6 pg mL(-1) (range 44.2-338.7 pg mL(-1)), respectively. On the other hand, no difference in bFGF plasma levels could be found between chronic-phase CML patients and the control group. There were significant associations between plasma VEGF levels and some characteristics of patients evaluated, with trends for higher VEGF values in patients with enlarged spleens (p = 0.02) and those with higher platelet count (p<0.001). Of the patients, 11 received imatinib treatment. The initial VEGF levels markedly decreased after 6 months of imatinib therapy in each patient (p<0.001). These data support the important pathophysiological role of VEGF in CML. Further studies aiming to explore the detailed angiogenic profile of CML may help in developing new therapeutic strategies for this myeloproliferative disorder.
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PMID:Elevated plasma levels of vascular endothelial growth factor is associated with marked splenomegaly in chronic myeloid leukemia. 1626 79

Artesunate (ART), a semi-synthetic derivative of artemisinin extracted from the Chinese herb Artemisia annua, is a safe and effective antimalarial drug. In the present investigation, we analyzed the inhibitory effects of ART on angiogenesis and on VEGF production in chronic myeloid leukemia (CML) K562 cells in vitro and in vivo. In order to analyze the effect of ART on VEGF secretion in K562 cells, we examined the level of VEGF secreted in conditioned media (CM) by ELISA assay. The result showed that ART could decrease the VEGF level in CM of K562 cells, even at a lower concentration (2 micromol/l, P<0.01). The inhibitory effect of in vitro angiogenesis was tested on aortic sprouting in fibrin gel. ART could effectively suppress the stimulating angiogenic ability of CM by pretreated with K562 cells for 48 h in a time-dependent manner (days 3-14). The antiangiogenic effect of ART was further evaluated in vivo in chicken chorioallantoic membrane (CAM) neovascularization model. The result indicated that the stimulating angiogenic activity was decreased in response to the K562 cells treated with ART or the CM from K562 cells pretreated with ART in a dose-dependent manner (3-12 micromol/l). Furthermore, we analyzed the level of VEGF expression by western blot and detected the form of VEGF mRNA by RT-PCR in K562 cells. The experiments showed that ART could inhibit the VEGF expression, correlated well with the level of VEGF secreted in CM. These findings suggest that ART might present potential antileukemia effect as a treatment for CML therapy, or as an adjunct to standard chemotherapeutic regimens.
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PMID:Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cells. 1758 94

Imatinib mesilate, which efficiently inhibits BCR-ABL,and KIT as well as platelet-derived growth factor receptor (PDGF-R) kinases, is highly effective for clinical treatment of CML, Ph+ALL, and advanced GIST with good tolerability, respectively. Acquired resistance to the drug,however, becomes an clinically emerging problem with long-standing use. Meanwhile, sunitinib malate,which inhibits three VEGF-Rs and FLT 3 in addition to KIT as well as PDGF-R, was clinically evaluated in the phase II clinical trials for imatinib-resistant or intolerant GIST, and advanced renal cell carcinoma in Japan. Sunitinib is therapeutically effective for both on imatinib-resistant GIST and advanced renal cell carcinoma with modest tolerability, and is now under review for approval in Japan.
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PMID:[Imatinib . Sunitinib]. 1768 1

The aim of this study was to investigate the inhibitive effect of artesunate (ART) on CML cell line K562 and its influence on VEGF expression in vitro. Human CML cell line K562 cells were cultured in RPMI 1640 medium supplemented with 10% heat-inactivated fetal calf serum. All cells were cultured in a humidified atmosphere of 5% CO2 at 37.0 degrees C. K562 cells in logarithmic growth phase were collected and seeded in RPMI-1640 medium, and were treated with ART. At the indicated time points, viable cells were counted by trypan blue exclusion method. Each assay was triplicated. K562 cells were treated with ART at different concentrations. Morphological changes were observed with invert microscope. VEGF expression in K562 cells treated with ART at different concentrations and in the control group were detected by enzyme-linked immunosorbent assay (ELISA). The results indicated that ART obviously induced growth inhibition in K562 cells. The relationship between cell inhibition rates and the concentrations of ART showed a dose-dependent manner (p < 0.01). VEGF expression of K562 cells treated with ART at different concentrations decreased significantly (p < 0.01). No significant change of VEGF expression in control group was observed (p > 0.05), while VEGF expression was down-regulated significantly in experiment groups (p < 0.01). The inhibition rate of K562 cells increased in time and concentration-dependent manners. In K562 cell lines treated with ART, VEGF expression was up-regulated at first and then down-regulated to a lower level. It is concluded that ART inhibits k562 cell proliferation in a dose and time dependent manner. The mechanism underlying the inhibitive effect of ART on K562 cells may be realized through down-regulation of VEGF expression.
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PMID:[Suppressive effect of artesunate on K562 cell growth and its influence on VEGF expression]. 1871 59

Cellular signal transduction pathways and gene expression are tightly regulated to accommodate changes in response to physiological environments. In the current study, molecules were identified that are activated as a result of intracellular signaling and immediately expressed as mRNA in MCF-7 breast cancer cells shortly after stimulation of ErbB receptor ligands, epidermal growth factor (EGF) or heregulin (HRG). For the identification of tyrosine-phosphorylated proteins and expressed genes, a SILAC (stable isotopic labeling using amino acids in cell culture) method and Affymetrix gene expression array system, respectively, were used. Unexpectedly, the overlapping of genes appeared in two experimental datasets was very low for HRG (43 hits in the proteome data, 1,655 in the transcriptome data, and 5 hits common to both datasets), while no overlapping gene was detected for EGF (15 hits in the proteome data, 211 hits in the transcriptome data, and no hits common to both datasets). The HRG overlapping genes included ERBB2, NEDD9, MAPK3, JUP and EPHA2. Biological pathway analysis indicated that HRG-stimulated molecular activation is significantly related to cancer pathways including bladder cancer, chronic myeloid leukemia and pancreatic cancer (p < 0.05). The proteome datasets of EGF and HRG contain molecules that are related to Axon guidance, ErbB signaling and VEGF signaling at a high rate.
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PMID:Phosphoproteome and transcriptome analyses of ErbB ligand-stimulated MCF-7 cells. 1882 Mar 70


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