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)

Chronic myeloid leukaemia (CML) is a stem cell disease characterized by an increased production and accumulation of clonal BCR/ABL-positive cells in haematopoietic tissues. The chronic phase of CML is inevitably followed by an accelerated phase of the disease, with consecutive blast crisis. However, depending on genetic stability, epigenetic events, and several other factors, the clinical course and survival appear to vary among patients. Recent data suggest that angiogenic cytokines such as vascular endothelial growth factor (VEGF), are up-regulated in CML, and play a role in the pathogenesis of the disease. These factors appear to be produced and released in leukaemic cells in patients with CML. In line with this notion, increased serum-levels of angiogenic growth factors are measurable in CML patients. In this study we provide an overview of angiogenic growth factors expressed in CML cells, discuss the possible pathogenetic role of these cytokines, the biochemical basis of their production in leukaemic cells, and their potential clinical implications.
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PMID:Expression of angiogenic factors in chronic myeloid leukaemia: role of the bcr/abl oncogene, biochemical mechanisms, and potential clinical implications. 1529 1

Human blood dendritic cells (DC) comprise plasmacytoid DC (PDC) and myeloid DC (MDC), which both prime antitumor T-cell responses. We prospectively monitored blood DC in 30 chronic myeloid leukemia (CML) patients before and after imatinib mesylate therapy. We found a dramatic reduction in PDC and MDC prior treatment. This reduction was associated with high plasmatic vascular endothelial growth factor (VEGF), a central regulator of angiogenesis which also participates to tumor-associated immune deficiencies. Phenotypic analysis of DC revealed in some patients a deficient expression of BDCA-4/neuropilin-1 on PDC, a molecule involved in angiogenesis and DC-T-cell interactions. High VEGF correlated to an altered Th1/Th2 balance in vivo and shifted PDC-induced T-cell polarization towards Th2 in vitro. Upon imatinib treatment, plasmatic VEGF rapidly decreased and a normal BDCA-4 expression was restored. PDC and MDC increased but did not reach the levels observed in healthy individuals. We conclude that VEGF may be a key player in blood DC deficiency in CML and we show that imatinib inhibits VEGF overproduction. Incomplete recovery of blood DC under imatinib despite VEGF normalization suggests a negative impact of this drug on dendritopoiesis in vivo and may result in a sustained defect in DC-mediated anti-CML responses.
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PMID:Defective blood dendritic cells in chronic myeloid leukemia correlate with high plasmatic VEGF and are not normalized by imatinib mesylate. 1534 47

Action of N(epsilon)-(carboxymethyl)lysine (CML) adduct, an advanced glycation end product, was investigated on neovascularization of cultured choroidal explants in streptozotocin (STZ)-diabetic rat. The choroidal explants of early (4 weeks after an injection of 60 mg/kg STZ) and advanced (8 months after the STZ injection) diabetic rats, and age-matched normal rats were cultured in fibrin gel with Dulbecco's modified Eagle medium containing fetal bovine serum. The number of budded microvessel-like structures was counted and used as an index of in vitro neovascularization. Choroidal explants in the early diabetic stage released vascular endothelial growth factor (VEGF) and tended to increase tumor necrosis factor (TNF) alpha and platelet-derived growth factor (PDGF)-B, and concomitantly facilitated growth of sprout and buds, compared to the normal control. When choroidal explants were stimulated with CML-human serum albumin (HSA), its releasing effect was in the order VEGF>TNFalpha>PDGF-B. CML-HSA and CML-bovine serum albumin augmented the neovascularization in the cultured diabetic explant and their actions did not virtually differ. A monoclonal anti-CML antibody (6D12) inhibited the neovascularization in the advanced diabetes greater than that in the early diabetes. Inhibitory actions of anti-VEGF and anti-TNFalpha antibodies on the neovascularization were similar to that of the anti-CML antibody in the diabetes. In conclusion, CML adducts were accumulated and over-produced the actions of VEGF, TNFalpha and PDGF-B in the choroidal explant during diabetes in an age-dependent manner. TNFalpha and VEGF are likely to play a predominant role for the CML-induced choroidal neovascularization.
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PMID:Overproduction of N(epsilon)-(carboxymethyl)lysine-induced neovascularization in cultured choroidal explant of streptozotocin-diabetic rat. 1546 96

We have previously reported that the Nepsilon (carboxymethyl)lysine (CML) adduct, a major structure of an advanced glycation end product, facilitates proliferation of CD34+ endothelial progenitor cells budded from cultured choroidal explants and produces immature vessel-like structures in fibrin gel. The CML adduct is accumulated and facilitates immature neovascularization in cultured choroidal explants of streptozotocin (STZ)-induced diabetic rat. The CML-enhanced neovascularization activity is associated with the actions of tumor necrosis factor (TNF) alpha, vascular endothelial growth factor and platelet-derived growth factor released from the choroidal explant (Kobayashi et al., Biol. Pharm. Bull., 27, 1382-1387 (2004); 27, 1565-1571 (2004)). The present study was investigated an inhibitory effect of a dihydropyridine calcium antagonist nifedipine on TNF alpha-induced choroidal neovascularization in the STZ-diabetic rat. TNF alpha (1-100 ng/ml) increased neovascularization of cultured choroidal explants in the age-matched normal rat but did not increase it in the diabetic rat. Anti-TNF alpha antibody (1 : 1000) decreased the neovascularization in the diabetic rat but not in the normal rat. Nifedipine (1 microM) inhibited TNF alpha-induced neovascularization of the normal choroidal explant in a non-competitive manner. Nifedipine (1 microM) also inhibited the diabetic state-induced neovascularization and its inhibitory action was reversed by TNF alpha (1-10 ng/ml). In conclusion, STZ-diabetic state facilitated choroidal neovascularization through the release of TNF alpha. Nifedipine inhibited the action of TNF alpha probably by blocking voltage-dependent Ca2+ channels in the endothelial progenitor cells of the diabetic choroid.
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PMID:Inhibitory effect of nifedipine on tumor necrosis factor alpha-induced neovascularization in cultured choroidal explants of streptozotocin-diabetic rat. 1568 77

The mammalian target of rapamycin (mTOR) has recently been described to be constitutively activated in Bcr-Abl-transformed cells and to mediate rapamycin-induced inhibition of growth in respective cell lines. We have recently shown that rapamycin down-regulates expression of vascular endothelial growth factor (VEGF), a mediator of leukemia-associated angiogenesis, in primary CML cells. In the present study, we analyzed growth-inhibitory in vitro and in vivo effects of rapamycin on primary CML cells and asked whether rapamycin-induced suppression of VEGF in leukemic cells is related to growth inhibition. Rapamycin dose dependently inhibited growth of primary CML cells obtained from patients with imatinib-responsive or imatinib-resistant disease as well as growth of Bcr-Abl-transformed imatinib-resistant cell lines. Moreover, we observed potent cytoreductive effects of rapamycin in a patient with imatinib-resistant Bcr-Abl+ leukemia. The growth-inhibitory effects of rapamycin on CML cells were found to be associated with G1 cell cycle arrest and with induction of apoptosis. In all cell types tested, rapamycin was found to down-regulate expression of VEGF. However, exogenously added VEGF did not counteract the rapamycin-induced decrease in proliferation. In conclusion, rapamycin inhibits growth of CML cells in vitro and in vivo and, in addition, down-regulates expression of VEGF. Both effects may contribute to the antileukemic activity of the drug in CML.
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PMID:Identification of mTOR as a novel bifunctional target in chronic myeloid leukemia: dissection of growth-inhibitory and VEGF-suppressive effects of rapamycin in leukemic cells. 1578 22

Meisoindigo, an active compound of a Chinese anti-leukemia medicine, has been effectively used in the treatment of chronic myelogenous leukemia (CML). Increasing evidences have demonstrated that angiogenesis is an important pathobiologic feature of CML. The anti-angiogenesis effect of meisoindigo on CML is unknown. In this study, we determined the effects of meisoindigo on the apoptosis, adherence and differentiation of endothelial cells as well as the secretion of vascular endothelial growth factor (VEGF) by CML cells. We found that VEGF level, measured by enzyme-linked immunosorbent assay (ELISA), was higher in bone marrow plasma from CML patients compared with the healthy controls (334.83+/-23.09 ng/L versus 102.36+/-38.76 ng/L, P<0.01). CML cell VEGF production was decreased after CML cells were treated with 10 micromol/L meisoindigo compared with the controls (212.10+/-46.13 ng/L versus 293.75+/-64.79 ng/L, P<0.05). Ten micromole per liter of meisoindigo could induce time-dependent apoptosis of ECV304 cells determined by annexin-V. Treatment of ECV304 cells with meisoindigo for 48 h reduced the number of adherent cells and the expression of VCAM-1 compared with the control cells (43.78+/-9.09% versus 73.51+/-3.21%, P<0.05). Meisoindigo also inhibited tubule formation of HUVECs in an in vitro Matrigel after HUVECs were incubated with meisoindigo for 6 h. Our findings suggest that meisoindigo could inhibit angiogeneic process through decreasing the VEGF secretion in leukemic cells and also through inhibiting the proliferation, adhesion and differentiation of endothelial cells, causing the interruption of a reciprocal stimulatory loop between leukemic and endothelial cells. This effect may contribute to the anti-leukemic effect of this drug.
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PMID:Anti-angiogenesis effects of meisoindigo on chronic myelogenous leukemia in vitro. 1598 34

The present study evaluated the serum levels of known angiogenic factors and analysed their prognostic significance in patients with acute or chronic leukemia. Enzyme-linked immunosorbent assays (ELISAs) were performed to quantify the basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), tumor necrosis factor-alpha (TNF-alpha), angiogenin, and matrix metalloproteinase-9 (MMP-9) in stored samples obtained before treatment from patients with acute myeloid leukemia (AML; 30 patients), acute lymphoblastic leukemia (ALL; 10 patients), and chronic myelogenous leukemia (CML; 14 patients). The levels of VEGF, HGF, angiogenin, and MMP-9 were all significantly higher in patients with CML than in healthy individuals. The HGF levels were also higher in patients with AML than in healthy individuals, plus there was a significant correlation between the HGF level and the white blood cell count, monocyte count, and serum level of lactate dehydrogenase (LDH) in patients with AML. In a univariate analysis, age and HGF level were both found to be significant parameters predictive for an achievement of complete remission (CR) in patients with AML. Meanwhile, in a multivariate analysis using a logistic regression model, the HGF level was the only parameter strongly predictive for CR (P=0.047). The leukemia-free survival (LFS) rate for AML patients with a lower HGF concentration was better than that for AML patients with a higher HGF concentration (1 year LFS rates=75.0% vs. 37.5%, P=0.065). The HGF concentration was an independent prognostic factor for an achievement of CR, plus higher HGF concentrations were associated with a lower survival in patients with AML.
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PMID:Clinical implications of angiogenic factors in patients with acute or chronic leukemia: hepatocyte growth factor levels have prognostic impact, especially in patients with acute myeloid leukemia. 1601 34

Dihydroartemisinin (DHA), a more water-soluble active metabolite of artemisinin derivatives, is safe and the most effective antimalarial analog of artemisinin. In the present investigation, we assessed the effect of DHA on vascular endothelial growth factor (VEGF) expression and apoptosis in chronic myeloid leukemia (CML) K562 cells. The results demonstrated that in addition to its antiproliferation effect on CML cells, DHA was also found to induce K562 cells apoptosis. The percentage of apoptotic cells was increased to 6.9 and 15.8% after being treated with 5 and 10 micromol/l DHA for 48 h, respectively (P<0.001). In order to analyze the effect of DHA on VEGF expression in K562 cells, we assessed the level of VEGF expression by western blot; detected the form of VEGF mRNA by RT-PCR and examined the level of VEGF secreted in conditioned media (CM) by ELISA assay. All these experiments suggested that DHA could inhibit the VEGF expression and secretion effectively in K562 cells, even at a lower concentration (2 micromol/l, P<0.05). Moreover, we further assessed the stimulating angiogenic activity of CM from K562 cells on CAM model. The angiogenic activity was decreased in response to the CM from K562 cells pretreated with DHA in a dose-dependent manner. Taken together, these results from our study together with its known low toxicity make it possible that DHA might present potential antileukemia effect as a treatment for CML therapy, or as an adjunct to standard chemotherapeutic regimens.
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PMID:Dihydroartemisinin downregulates vascular endothelial growth factor expression and induces apoptosis in chronic myeloid leukemia K562 cells. 1607 80

Increased angiogenesis has been demonstrated to be a significant prognostic factor in many solid tumors. In the oncohematological setting, it has been associated with myelodysplastic syndromes (MDS), chronic myeloid leukemia, acute lymphoid, and myeloid leukemias. Recently, increased circulating endothelial cells (CECs) have been associated with breast cancer and non-Hodgkin lymphoma (NHL). Based on these premises we analysed total and activated CECs, and endothelial precursors (CEPs) in 50 MDS patients and 20 healthy donors. CECs and CEPs were quantified by flow cytometry. CEC levels were compared with bone marrow (BM) microvessel density (MVD). In addition, some angiogenic factors, namely vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and soluble VEGF-Receptor2 (VEGFR2), were tested in the sera from 25 MDS patients. Total, activated CECs and CEPs were significantly increased in MDS when compared to control group (p<0.0001); whereas in the MDS cases no association was found with French--American--British (FAB), International Prognostic Scoring System (IPSS) subtypes or survival. Patients with higher CECs also showed higher MVD. Among the cytokines analysed, sVEGFR2 was significantly higher in the lower IPSS risk classes, while the levels of bFGF directly correlated with total and activated CECs. Taken together these data strengthen the hypothesis of a possible role of angiogenesis in MDS pathogenesis.
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PMID:Endothelial precursors and mature endothelial cells are increased in the peripheral blood of myelodysplastic syndromes. 1610 13

To explore the effects of vascular endothelial growth factor (VEGF) on the mechanisms of CML pathogenesis, the effect of VEGF on K562 cell apoptosis induced by As(2)O(3) was analyzed through morphologic observation, DNA fragmentation agarose gel electrophoresis and DNA ploidy flow cytometry analysis, and the effect of VEGF on the expression of bcl-X(L), Bax and caspase-3 in K562 cells was determined by Western blot, meanwhile the expression difference between bcl-X(L) and Bax mRNA in above conditions was detected by RT-PCR. The results showed that after VEGF added, the apoptosis of K562 cells reduced, however, there was no significant changes in cell cycle distribution (P > 0.05). At the same time, following the increasing of the concentration of VEGF, expression of mRNA and protein of bcl-X(L) was up-regulated and the expression of Bax protein was down-regulated in K562 cells, and the activation of pro-caspase-3 into caspase-3 was inhibited or reduced. It is concluded that VEGF may suppress the apoptosis of K562 cells through its influence on the bcl-X(L)/Bax expression ratio in K562 cells.
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PMID:[Anti-apoptosis effect of VEGF on the human chronic myelocytic leukemia cell line K562]. 1627 41


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