Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We demonstrated in this study that inhibition of intra-hepatic growth of colon cancer by TAC-101 is mediated by inhibition of angiogenesis. In vitro experiments showed that TAC-101 inhibited the proliferation of murine hepatic sinusoidal endothelial (HSE) cells induced by coculture with murine colon 26-L5 (L5) cells. HSE cell proliferation was also enhanced by conditioned medium of L5 cells (CM-L5), and this enhancement of proliferation was abrogated by anti-vascular endothelial growth factor antibody. CM-L5 also induced in vitro tube formation of HSE cells on Matri-gel, and this activity of CM-L5 was abrogated by TAC-101 in a concentration-dependent manner. On the other hand, p.o. administration of TAC-101 inhibited tumor-induced angiogenesis in vivo and decreased the weights of L5 tumors in the mouse liver. Reverse transcriptase-PCR analysis using in vivo tumor tissue suggested that repression of vascular endothelial growth factor expression by TAC-101 was associated with the antiangiogenic activity. TAC-101 alone and 5-fluorouracil (5-FU)/D,L-leucovorin (LV) significantly inhibited the intrahepatic growth of L5 tumors (P = 0.002 and 0.001, respectively), whereas 5-FU alone did not (P = 0.088). When TAC-101 was administered with 5-FU/LV, marked enhancement of antitumor activity was observed (95% inhibition; P<0.001). This enhanced antitumor effect was also observed in experiments using Co-3 human colon adenocarcinoma. Concurrent treatment with TAC-101 and 5-FU/LV and sequential treatment with 5-FU/LV followed by TAC-101 resulted in significant augmentation of antitumor activity against Co-3 (overall P = 0.007 and 0.015, respectively). These findings indicate that TAC-101 inhibits tumor angiogenesis and suggest that it may be effective against hepatic metastasis of colon cancer.
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PMID:Inhibition of angiogenesis and intrahepatic growth of colon cancer by TAC-101. 1049 97

Primary effusion lymphomas (PELs), which are rare lymphomas associated with Kaposi's sarcoma-associated herpesvirus (or human herpesvirus-8) infection, present as malignant lymphomatous effusions in body cavities. Because PELs prefer liquid growth, we hypothesized that increased vascular permeability would be required for effusions to form. We found that the PEL cell lines BC-1, BCP-1, and BCBL-1 produce high levels of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). Reverse transcriptase-polymerase chain reaction analysis of RNA from the PEL cell lines amplified the 3 VEGF-secreted isoforms: VEGF/VPF(121), VEGF/VPF(145), and VEGF/VPF(165). Two of the PEL cell lines expressed the VEGF/VPF receptor Flt-1, but VEGF/VPF did not stimulate proliferation in these cells. Most (13/14) control SCID/beige mice inoculated intraperitoneally with BCBL-1 cells and subsequently observed or treated with control antibodies developed effusion lymphoma of human cell origin with prominent bloody ascites. In contrast, none (0/9) of the mice treated with a neutralizing antihuman VEGF/VPF antibody developed ascites and effusion lymphoma. These results demonstrate that VEGF/VPF is critical to BCBL-1 growth as effusion lymphoma in mice and suggest that VEGF/VPF stimulation of vascular permeability may be critical to the pathogenesis of PELs.
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PMID:Role of vascular endothelial growth factor/vascular permeability factor in the pathogenesis of Kaposi's sarcoma-associated herpesvirus-infected primary effusion lymphomas. 1059 69

Because the crucial role of angiogenesis has been demonstrated in tumor growth and metastasis, the present study was undertaken to characterize the relative expression of vascular endothelial growth factors VEGF (vascular endothelial growth factor), VEGF-B, VEGF-C, and their receptors KDR (kinase insert domain-containing receptor), FLT-1 (fms-like tyrosine kinase), and FLT-4 in human colonic cancers, in relation to the Astler-Coller pathological classification, and to prognosis. VEGF and VEGF-B gene expression was quantified by Northern blot in 72 tumor samples matched with control tissues. VEGF gene expression was 1.4 times higher in adenocarcinomas than in control tissues (p = 0.02), but did not increase further between Astler-Coller tumor stages A and D, and did not correlate with disease recurrence for patients at stages B2 or C. In adenomas, VEGF mRNA levels were not significantly different from those in the paired control colonic mucosa. The expression pattern of VEGF isoforms, mainly identified by RT-PCR (reverse-transcriptase-coupled polymerase chain reaction) as VEGF121 and VEGF165 and to a lesser extent VEGF189, was comparable in tumor and control tissues. VEGF-B mRNA levels were unchanged during the neoplastic progression of colonic mucosa. In contrast to KDR and FLT-4, the expression of VEGF-C and FLT-1 genes increased in some pathological tissues. These results provide evidence that the early and sustained increase in VEGF transcripts and the expression of multiple angiogenic factors and receptors contribute to the development of colon cancer, and thus constitute a putative target for anti-angiogenic drug therapy.
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PMID:Vegf, Vegf-B, Vegf-C and their receptors KDR, FLT-1 and FLT-4 during the neoplastic progression of human colonic mucosa. 1073 43

To gain insight into the glomerular capillary repair mechanisms in immunoglobulin A (IgA) nephropathy, we focused on vascular endothelial growth factor (VEGF-A) and nitric oxide (NO). Because abnormal glycosylation of serum IgA has been shown in IgA nephropathy, we examined whether VEGF-A and NO production by mesangial cells (MCs) could be modulated by aberrantly glycosylated (desialylated or degalactosylated) IgA. VEGF-A and NO synthase (NOS) gene expression were examined by reverse-transcriptase polymerase chain reaction (RT-PCR) or Northern blot analysis, and VEGF-A peptide, by capture enzyme-linked immunosorbent assay and NOS activity as production of tritium ([(3)H]) citrulline from [(3)H] arginine. Semiquantitative densitometric analysis of RT-PCR experiments showed a significant downregulation of VEGF-A messenger RNA (mRNA) in MCs incubated with aberrantly glycosylated IgA. This resulted in decreased release of VEGF-A in culture medium (P: < 0. 01). NOS activity and inducible NOS (iNOS) mRNA were enhanced by aberrantly glycosylated IgA (both P: < 0.01). No modulation of constitutive NOS mRNA was found. The depression of the VEGF-A production induced by aberrantly glycosylated IgA was mediated by NO because it was completely reversed by the NOS inhibitor, N:omega-nitro-L-arginine methyl ester. The NO donor, sodium nitroprusside, induced a bimodal modulation of VEGF; although low concentrations (0.0001 nmol/L) increased VEGF-A synthesis, greater concentrations (1,000 nmol/L) depressed it. In conclusion, we report negative control of VEGF-A synthesis in MCs by aberrantly glycosylated IgA, mediated by enhanced iNOS activity. We speculate that both increased iNOS activity and depressed VEGF-A synthesis might have a role in impairing vascular repair and favor sclerosis in IgA nephropathy.
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PMID:Aberrantly glycosylated IgA molecules downregulate the synthesis and secretion of vascular endothelial growth factor in human mesangial cells. 1109 49

The vascular endothelial growth factor is produced by a large variety of human tumors, including melanoma, in which it appears to play an important role in the process of tumor-induced angiogenesis. Little information is available on the role of placenta growth factor, a member of the vascular endothelial growth factor family of cytokines, in tumor angiogenesis, even though placenta growth factor/vascular endothelial growth factor heterodimers have been recently isolated from tumor cells. To investigate the role of placenta growth factor and vascular endothelial growth factor homodimers and heterodimers in melanoma angiogenesis and growth, 19 human melanoma cell lines derived from primary or metastatic tumors were characterized for the expression of these cytokines and their receptors. Release of placenta growth factor and vascular endothelial growth factor polypeptides into the supernatant of human melanoma cells was demonstrated. Reverse transcriptase polymerase chain reaction analysis showed the presence of mRNAs encoding at least three different vascular endothelial growth factor isoforms (VEGF(121), VEGF(165), and VEGF(189)) and transcripts for two placenta growth factor isoforms (PlGF-1 and PlGF-2) in human melanoma cells. In addition, placenta growth factor expression in human melanoma in vivo was detected by immunohistochemical staining of tumor specimens. Both primary and metastatic melanoma cells were found to express the mRNAs encoding for vascular endothelial growth factor and placenta growth factor receptors (KDR, Flt-1, neuropilin-1, and neuropilin-2), and exposure of melanoma cells to these cytokines resulted in a specific proliferative response, supporting the hypothesis of a role of these angiogenic factors in melanoma growth. J Invest Dermatol 115:1000-1007 2000
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PMID:Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. 1112 Nov 33

Microvessel density (MVD) was estimated in a series of 202 vertical growth phase (VPG) melanomas and 68 corresponding metastases, using a marker for angiogenic endothelial cells (CD105) and Factor-VIII. The expression pattern of vascular endothelial growth factor (VEGF), FLT-1, KDR and thrombospondin-1 (TSP-1) was studied by immunohistochemistry, in situ hybridization and reverse-transcriptase polymerase chain reaction. CD105 stained significantly less vessels, but gave only limited additional prognostic information compared with Factor-VIII, and MVD was an independent prognostic factor for both markers. Ninety-eight percent of all cases showed expression of VEGF, and higher expression was found significantly more frequent in thinner and less vascularized tumors. Possible autocrine loops were suggested by co-expression of VEGF and its two receptors in tumor cells, and by a significant correlation between KDR and tumor cell proliferation (Ki-67) in the subgroup of thicker tumors. Staining of VEGF receptors in endothelium was not correlated with MVD. Strong expression of TSP-1 in tumor stroma was found in 43% of the primary tumors, and was significantly correlated with increased thickness, proliferation and MVD, as well as decreased survival. These data suggest that MVD is associated with prognosis in cutaneous melanomas, and that the VEGF system and particularly TSP-1 seem to be involved in the regulation of angiogenesis and progression of these tumors.
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PMID:Expresson of vascular endothelial growth factor, its receptors (FLT-1, KDR) and TSP-1 related to microvessel density and patient outcome in vertical growth phase melanomas. 1143 69

Platelet-activating factor (PAF) is a lipid mediator that stimulates the in vitro growth of various human tumour cell lines and that enhances the effect of vascular endothelial growth factor that plays a key role during angiogenesis of human cancer. In this study, we assessed the levels of PAF and of the acetylhydrolase activity (AHA, the PAF degrading enzyme) in patients with lung cancer. Results indicated no significant differences between blood PAF amounts of lung cancer patients (91+/-33 pg/ml, n=31) and a control group of patients with chronic obstructive pulmonary disease (COPD) induced by habitual smoking (117+/-28 pg/ml, n=10). Similarly, their serum AHA levels were not different (67.9+/-3.0 nmol/min/ml as compared to 68.3+/-5.2 nmol/min/ml for lung cancer patients and controls, respectively). In contrast, PAF amounts were markedly (P=0.01, t-test for paired data) reduced in the lung tumour tissues (77+/-29 pg/g, n=10) as compared to the non-tumour tissues (208+/-67 pg/g, n=10). These low levels of PAF were not related to a lower amounts of the lyso-PAF precursor but to an elevated (P=0.01, t-test for paired data) AHA in the tumour tissues (37.0+/-4.9 nmol/min/g, n=10) as compared to the non-tumour tissues (24.6+/-2.6 nmol/min/ml, n=10). Reverse transcriptase polymerase chain reaction experiments showed the presence of the PAF receptor (PAF-R) transcript 1 but not transcript 2 in blood mononuclear cells of lung cancer patients and COPD patients. Flow cytometry experiments did not highlight differences in the number and the distribution of PAF-R on their circulating leukocytes. In conclusion, this clinical study highlights no evidence for a potential important role of PAF during human lung cancer.
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PMID:Is there a role of platelet-activating factor in human lung cancer? 1155 14

The Achilles tendon is one of the most common sites of injury and rupture. Evidence suggests that local vascularisation is involved in this aetiology. We investigated the expression of one important angiogenic factor, the vascular endothelial growth factor (VEGF), in normal and pathologic human Achilles tendons using immunohistochemical, biochemical, molecular and cell biology methods. VEGF could be immunostained in tenocytes of ruptured and foetal Achilles tendons, but not in normal adult ones. In microvessels, the VEGF receptor VEGFR-1 (flt-1) could be visualised as well. High VEGF levels were measured in homogenates from ruptured adult, lower ones in foetal and negligible concentrations in normal adult Achilles tendons using enzyme-linked immunoassay (ELISA) and Western blot experiments. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed that the splice variants VEGF121 and VEGF165 are exclusively expressed. In tenocytes cultivated from newborn rat Achilles tendons, hypoxia or epidermal growth factor (EGF) raised VEGF production moderately whereas their combination resulted in a strong, synergistic induction. These results prove the presence of an angiogenic peptide and vascularisation in ruptured and foetal tendons and support the view that microtrauma or degeneration in the Achilles tendon precedes its rupture.
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PMID:The angiogenic peptide vascular endothelial growth factor is expressed in foetal and ruptured tendons. 1171 Jun 46

Extensive evidence demonstrates pronounced effects of relaxin on the differentiation of human endometrial cells in vitro. In vivo data in rhesus monkeys suggest a role for relaxin in the development of endometrial vascular architecture. In women, pregnancy can be established and maintained in the absence of circulating relaxin. Thus, local synthesis by the endometrium is necessary if relaxin plays a physiological role in human endometrial function. Although relaxin protein and the prorelaxin C peptide have been localized to human endometrium, no data for relaxin synthesis have been provided to date. We therefore assessed relaxin mRNA and protein levels in cultured, defined human endometrial cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) techniques were used to demonstrate the presence of relaxin mRNA in human stromal and glandular epithelial cells. Secretion of the protein into the media of cultured cells of both types was also detected. Relaxin stimulated the expression of vascular endothelial growth factor in glandular epithelial and stromal cells that were isolated from tissue that had been taken during the secretory phase of the cycle. Relaxin inhibited the expression of procollagenase from both glandular epithelial cells, with a more marked inhibition demonstrated from cells that were isolated from tissue that had been taken during the secretory phase, and from stromal cells. These data demonstrate that human endometrial cells synthesize relaxin, and they support the concept that relaxin fosters endometrial conditions that are required for implantation in women.
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PMID:Relaxin gene and protein expression and its regulation of procollagenase and vascular endothelial growth factor in human endometrial cells. 1202 Oct 56

Interaction between ephrinB2 and EphB4 in endothelial cells at the arterial-venous capillary interface is critical for proper embryonic capillary morphogenesis. However, the intracellular downstream signaling of ephrinB2-EphB in vascular endothelial cells is unknown. This study examined the effect of ephrinB2-induced activation of EphB kinases on vascular endothelial growth factor (VEGF)- and angiopoietin-1 (Ang1)-induced Ras/mitogen-activated protein kinase (MAPK) signaling cascades in human umbilical vein endothelial cells (HUVECs). Reverse transcriptase-polymer chain reaction results showed that HUVECs expressed three kinds of EphB kinases known to bind to ephrinB2: EphB2, EphB3, and EphB4. EphrinB2 not only increased the phosphorylation of EphB2 and EphB4 in a time-dependent manner but also increased recruitment of p120-Ras-GTPase-activating protein (p120-RasGAP) to EphB2 and EphB4. Accordingly, ephrinB2 inhibited VEGF- and Ang1-induced Ras-MAPK activities, whereas ephrinB2 did not alter VEGF-induced Flk phosphorylation or Ang1-induced Tie2 phosphorylation. Furthermore, ephrinB2 suppressed VEGF- and Ang1-induced proliferation and/or migration, which are mediated mainly through Ras/MAPK signaling cascades. From these results, we propose that ephrinB2-EphB, signaling through Ras/MAPK cascade, may be critical for proper morphogenesis of capillary endothelium through the arrest of endothelial cell proliferation and migration at the arterial-venous interface.
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PMID:EphB ligand, ephrinB2, suppresses the VEGF- and angiopoietin 1-induced Ras/mitogen-activated protein kinase pathway in venous endothelial cells. 1203 42


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