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)

Vascular endothelial growth factor (VEGF) and placental derived growth factor (PlGF) stimulate cell proliferation and differentiation by binding to their specific receptors, Flk-1/KDR and Flt-1 respectively. Flk-1/KDR-deficient murine embryos manifest failure of blood-island formation and vasculogenesis. The aim of this study was to directly evaluate the importance of VEGF, PlGF/Flt-1 and Flk-1/KDR receptor ligand interactions in regulating normal and malignant human haemopoiesis. Addition of VEGF and PlGF failed to enhance survival or cloning efficiency of human haemopoietic progenitors isolated from adult bone marrows, fetal livers or cord blood samples. This finding may be explained by the apparent absence of mRNA encoding Flt-1 and Flk-1/KDR receptors on stem cell rich CD34+ c-kit-R+ Rh123(low) cells. Further studies revealed that Fit-1 R mRNA, but not Flk-1/KDR mRNA was first detectable in the more mature cells isolated from haemopoietic colonies. Accordingly, VEGF receptors are either absent, or expressed at very low level, on human haemopoietic stem/progenitor cells. Of interest, normal and malignant human haemopoietic cells appeared to secrete VEGF protein. However, in contrast to normal haemopoietic progenitors, VEGF co-stimulated HEL cell proliferation as well as CFU-GM colony formation from approximately 15% of the chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) patients studied. Therefore, although VEGF appeared to have minimal effects on normal haemopoietic cell growth it would appear to drive malignant haemopoietic cell proliferation to some degree. Of more importance, however, we speculate that VEGF may play an very important role in leukaemogenesis by stimulating growth of vascular endothelium, thereby providing a sufficient blood supply to feed the growing haematological tumour.
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PMID:Role of vascular endothelial growth factor (VEGF) and placenta-derived growth factor (PlGF) in regulating human haemopoietic cell growth. 988 8

Vascular endothelial growth factor (VEGF) is a specific mitogen for vascular endothelial cells. It has been associated with angiogenesis, growth, metastasis and poor prognosis in solid tumors. Lately, it has been known that VEGF expression is higher in bone marrow from chronic myeloid leukemia (CML) patients than that in normal subjects. However, it is not clarified that the effect of VEGF on the abnormal proliferation of CML cells. In order to explore the effect of autocrine VEGF on CML cells, K562 cells were transfected with the VEGF(121) cDNA sense vector (K562/S) or with the VEGF(121) cDNA antisense vector (K562/As). K562 cells were transfected with the pcDNA(3) vector (K562/V) as the control. Cell proliferation was determined by MTT and colony forming assay in vitro. Flow cytometric Annexin-V-FITC/PI dual labeling technique was performed to observe the effect of VEGF(121) cDNA transfection on apoptosis of K562 cells. Results indicated that K562/S transfectants exhibited a 3-fold increase in VEGF secretion, and K562/As transfectants exhibited a 49% reduction in VEGF secretion. K562/As showed a reduced growth rate and colony forming efficiency as compared to K562/V. K562/S showed an increasing growth rate and colony forming efficiency as compared to K562/V. K562/As had more apoptotic cells than K562/V and K562/S in the same culture condition. These data suggest that VEGF plays an important role in the abnormal proliferation and apoptosis in CML cells through an autocrine mechanism.
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PMID:[Effect of Autocrine VEGF on Chronic Myeloid Leukemia Cell Line K562] 1257 89

Vascular endothelial growth factor (VEGF) is one of the main angiogenic cytokines and plays an important role in the development of human solid tumors. However, it is not clarified whether VEGF governs the progress of the chronic myelogenous leukemia (CML). This study is to estimate VEGF expression in the bone marrow cells from normal and adult CML patients and various leukemic cell lines. Reverse transcription-polymerase chain reaction (RT-PCR) was used for detection of VEGF mRNA. VEGF concentrations in the cell cultural supernatant and the plasma from normal and CML patient bone marrows were determined by enzyme linked immunosorbent assay (ELISA). VEGF mRNA was positive in 67 of 72 cases of bcr/abl(+) CML patient bone marrow cells (93.1%), in 5 of 10 CML patients post Allo-BMT bone marrow cells (50%), and in 6 of 10 normal bone marrow cells (60%), the expression rate of VEGF mRNA in CML patients bone marrow cells was higher than that in CML patients post Allo-BMT and normal bone marrow cells. VEGF mRNA also expressed in the HL-60, K562, CEM, KG1a, NB4, and Nalm6 cells, but not in the Jurkat cells. The mean VEGF concentration in the plasma (380.6 pg/ml) from 22 untreated CML patients was 9 folds higher than that from 9 CML patients post Allo-BMT (38.0 pg/ml). The mean VEGF concentration in the cultural supernatant (499.8 pg/ml) of 17 newly diagnosed CML bone marrows was 2.5-folds higher than that in 11 normal donors (141.3 pg/ml). The CML marrow cells secrete more VEGF than normal marrow cells do. Our results suggest that the abnormality of VEGF transcription and translation expression may play an important role in the development of CML.
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PMID:[Expression of Vascular Endothelial Growth Factor in the Bone Marrow Cells from Adult Chronic Myelogenous Leukemia] 1257 35

Receptor and non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating gastrointestinal cancer. Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl TK, which was primarily designed to treat chronic myeloid leukemia is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. The epidermal growth factor receptor (EGFR), which is involved in cell proliferation, metastasis and angiogenesis, is another important target. The two main classes of EGFR inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, Iressa(TM)) has been on trial for esophageal and colorectal cancer (CRC) and erlotinib (OSI-774, Tarceva(TM)) on trial for esophageal, colorectal, hepatocellular, and biliary carcinoma. In addition, erlotinib has been evaluated in a Phase III study for the treatment of pancreatic cancer. Cetuximab (IMC-C225, Erbitux(TM)), a monoclonal EGFR antibody, has been FDA approved for the therapy of irinotecan resistant colorectal cancer and has been tested for pancreatic cancer. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis. Bevacizumab (Avastin(TM)), a monoclonal antibody against VEGF, was efficient in two randomized clinical trials investigating the treatment of metastatic colorectal cancer. It is also currently investigated for the therapy of pancreatic cancer in combination with gemcitabine. Other promising new drugs currently under preclinical and clinical evaluation, are VEGFR2 inhibitor PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777 (tipifarnib, Zarnestra(TM)), matrix metalloproteinase inhibitors, proteasome inhibitor bortezomib (Velcade(TM)), mammalian target of rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, platelet derived growth factor receptor (PDGF-R) inhibitors, protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors, Rous sarcoma virus transforming oncogene (SRC) kinase inhibitors, histondeacetylase (HDAC) inhibitors, small hypoxia-inducible factor (HIF) inhibitors, aurora kinase inhibitors, hedgehog inhibitors, and TGF-beta signalling inhibitors.
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PMID:Molecularly targeted therapy for gastrointestinal cancer. 1589 18

Vascular endothelial growth factor (VEGF) is produced in neoplastic cells in various myeloid neoplasms and may act as an autocrine growth-regulator. We have examined the expression of five VEGF receptors (VEGR1/Flt-1, VEGFR2/KDR, Flt-4, neuropilin-1 = NRP-1, NRP-2) in leukemic cells obtained from patients with acute myeloid leukemia (n = 28), chronic myeloid leukemia (n = 14), chronic eosinophilic leukemia (n = 3), chronic myelomonocytic leukemia (n = 9), or mast cell leukemia/systemic mastocytosis (n = 3) as well as in respective cell lines. Expression of VEGFR mRNA was analyzed by RT-PCR, and expression of VEGFR protein by immunocytochemistry. In most patients, leukemic cells expressed NRP-1 mRNA and NRP-2 mRNA independent of the type of disease. By contrast, transcripts for Flt-1, KDR, and Flt-4 were expressed variably without a clear correlation to the type of leukemia. Expression of VEGF receptors was also demonstrable at the protein level in all cases tested. In conclusion, neoplastic cells in myeloid leukemias frequently express VEGFR including NRP-1 and NRP-2.
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PMID:Myeloid leukemias express a broad spectrum of VEGF receptors including neuropilin-1 (NRP-1) and NRP-2. 1791 67

Although imatinib mesylate (IM) in the treatment of chronic myelogenous leukemia (CML) remains the best example of successful targeted therapy, majority of patients with CML suffer its toxicity profile and develop chemoresistance to existing therapeutic agents. Thus, there is a need to develop novel alternative therapies for the treatment of CML. Here, we investigated whether Korean red ginseng extract (KRGE) could suppress the proliferation and induce chemosensitization in human CML cells. Also, we used a human phospho-antibody array containing 46 antibodies against signaling molecules to examine a subset of phosphorylation events after treatment. Korean red ginseng extract broadly suppressed the proliferation of five different cell lines, but KRGE was found to be the most potent inducer of apoptosis against KBM-5 cells. It also abrogated the expression of Bcl-2 (B-cell lymphoma 2), Bcl-xL (B-cell lymphoma-extra large), survivin, inhibitors of apoptosis protein 1/2, COX-2 (Cyclooxygenase-2), cyclin D1, matrix metalloproteinase-9, and VEGF (Vascular endothelial growth factor), as well as upregulated the expression of pro-apoptotic gene products. Interestingly, KRGE also enhanced the cytotoxic and apoptotic effect of IM in KBM-5 cells. The combination treatment of KRGE and IM caused pronounced suppression of p38 and signal transducer and activator of transcription 5 phosphorylation and induced phosphorylation of p53 compared with the individual treatment. Our results demonstrate that KRGE can enhance the anticancer activity of IM and may have a substantial potential in the treatment of CML.
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PMID:Korean Red Ginseng Extract Enhances the Anticancer Effects of Imatinib Mesylate Through Abrogation p38 and STAT5 Activation in KBM-5 Cells. 2585 79