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: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report that cytosine arabinoside (Ara-C), a cytosine analogue that at low doses causes phenotypical changes on human leukemia cells in vitro and in vivo, induces growth inhibition of oropharyngeal cancer KB and lung adenocarcinoma A549 cell lines. An increase in the number of epidermal growth factor and transferrin receptors (EGFR, TrfR) is induced by Ara-C on these cells. Maximal EGFR up-regulation occurs 96 h after the beginning of Ara-C exposure while maximal TrfR up-regulation is detected 24 h later. These effects occur without changes in the affinity of EGFR and TrfR for their ligands. Two classes of EGF-binding sites with a Kd of 0.055 nM and 2.3 nM respectively, and one class of transferrin-binding sites with a Kd of about 4 nM are detected on both untreated and Ara-C-treated KB cells. [3H]Thymidine uptake is clearly stimulated on KB cells by nanomolar concentrations of EGF and transferrin, whereas in Ara-C-treated cells [3H]thymidine uptake is not increased by EGF and transferrin under conditions where maximal EGFR and TrfR up-regulation occurs. The enhanced EGF and transferrin binding is paralleled by a twofold increase of in vitro targeting of Ara-C-treated KB and A549 cells with anti-EGFR 108.1 mAb and anti-TrfR OKT9 mAb. We propose that Ara-C could provide a new approach for the improvement of the therapeutic index of anti-EGFR and anti-TrfR immunoconjugates.
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PMID:Cytosine arabinoside increases the binding of 125I-labelled epidermal growth factor and 125I-transferrin and enhances the in vitro targeting of human tumour cells with anti-(growth factor receptor) mAb. 839 10

Changes in protein phosphorylation in the human colon carcinoma cell line LIM 1215 after stimulation with epidermal growth factor (EGF) have been analyzed by two-dimensional gel electrophoresis and phosphoamino acid analysis. In addition to a number of tyrosine-phosphorylated proteins, a family of small proteins (M(r) 19,000-20,000) is maximally phosphorylated on serine within 5 min of EGF stimulation. One member of the family has been purified by a combination of two-dimensional electrophoresis and reversed-phase high performance liquid chromatography and identified by amino acid sequence analysis as stathmin. Although phosphorylation of stathmin has been reported previously in leukemia cells and following stimulation of hemopoietic or lymphoid cells with several mitogenic agents, this is the first report of stathmin phosphorylation in response to EGF.
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PMID:Epidermal growth factor induces serine phosphorylation of stathmin in a human colon carcinoma cell line (LIM 1215). 851 77

Uterine epithelial cells (UEC) isolated from 6-week-old CF-1 mice were immortalized using retroviral-mediated transfection of SV40 large T-antigen. One line, WEG-1, retained epithelial morphology and reacted with antibodies to cytokeratins 18, 19, laminin, fibronectin, and beta-catenin. In addition, WEG-1 cells displayed strong nuclear immunoreactivity to SV40 large T-antigen, confirming integration of the retrovirus vector and expression of this gene. WEG-1 cells were negative for nonepithelial markers such as desmin and factor 8. WEG-1 cells did not proliferate in serum-free medium; however, addition of 0.5% FBS supported proliferation to the same extent as 10% FBS. Addition of 50 ng/ml epidermal growth factor to medium containing 0.5% charcoal-stripped FBS restored proliferation comparable with 0.5% whole FBS. Epidermal growth factor or transforming growth factor-alpha (50 ng/ml), but not transforming growth factor-beta, leukemia-inhibiting factor, or fibroblast growth factor, induced the secretion of three proteins (M(r) approximately to 158K, 148K, and 36K). Comparison of protein secretions of WEG-1 cells and UEC showed shared as well as distinct bands. Like UEC, WEG-1 cells secreted PGF2a and PGE2 and expressed PG GH synthase-2. Unlike UEC, WEG-1 cells showed no apical/basal preference for either uptake of methionine or secretion of proteins. The absence of immunoreactive E-cadherin or zona occludens-1 was consistent with the absence of cell polarity in WEG-1 cells. Primary UEC, which polarize in vitro, do not support blastocyst attachment. WEG-1 cells, although not polarized in vitro, also exhibited delayed blastocyst attachment compared with nonuterine cell lines, suggesting that WEG-1 cells partially retained some aspects of UEC function relevant to embryo attachment. WEG-1 cells expressed messenger RNA for Muc-1, an UEC mucin suggested to have antiadhesive properties. Furthermore, WEG-1 cells did not display high affinity heparin binding sites, an activity associated with embryo attachment. WEG-1 cells may provide a model for studying various aspects of UEC function and murine embryo attachment.
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PMID:Production and characterization of WEG-1, an epidermal growth factor/transforming growth factor-alpha-responsive mouse uterine epithelial cell line. 853 10

Prostate tumor cells preferentially metastasize to bony sites and lymph nodes at a frequency in excess of that which would be predicted by random tumor cell dissemination. In order to determine whether chemoattractants in these organs promote organ-specific metastasis, we utilized human cell lines derived from and/or related to these organs as sources of potential chemoattractants. Secretory proteins derived from the cell lines MG-63 (osteosarcoma), SK-ES-1 (Ewing's sarcoma), and KG-1 (leukemia) stimulated chemomigration of the TSU-pr1 prostate tumor cells in a dose-dependent manner in Boyden chambers. In addition, secretory proteins from a human prostatic stromal cell line (hPS) and from the TSU-Pr1 prostate tumor cell line were also able to stimulate chemomigration of the TSU-pr1 cells through Boyden chambers. Since lymph nodes and bony sites represent organs of hematopoietic/lymphoid proliferation and activation, we undertook identification of specific cytokines present at these sites which may promote the chemomigration of prostate tumor cells. In this context, the cytokines interleukin-1 alpha, interleukin-2, interleukin-6, tumor necrosis factor-beta, transforming growth factor-beta, interferon alpha 2-a, and granulocyte-macrophage colony-stimulating factor did not stimulate chemomigration of the TSU-pr1 prostate tumor cell line. In contrast, the cytokine epidermal growth factor (EGF) stimulated chemomigration of the TSU-pr1 prostate tumor cells through the Boyden chambers in a dose-dependent manner. Western blot analysis of secretory proteins from the cell lines KG-1, SK-ES-1, MG-63, hPS, and TSU-pr1 identified EGF-immunoreactive proteins in all cases. In addition, EGF immunoreactivity was localized to the stroma of the human prostate, the osteogenic stroma of pelvic medullary bone, and the stroma within the capsule and trabeculae of pelvic lymph nodes. Hence, these results demonstrate that the cytokine EGF promotes the chemomigration of the TSU-pr1 prostate tumor cell line, and that EGF within the stroma of pelvic lymph nodes and medullary bone may act as a chemoattractant for prostate tumor cells, thereby facilitating the preferential formation of metastatic foci within these organs.
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PMID:Epidermal growth factor (EGF) promotes chemomigration of a human prostate tumor cell line, and EGF immunoreactive proteins are present at sites of metastasis in the stroma of lymph nodes and medullary bone. 854 75

We have examined basal and lipopolysaccharide (LPS)-induced release of epidermal growth factor (EGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), growth-regulated peptide alpha (GRO alpha), leukaemia inhibitory factor (LIF), macrophage inflammatory protein-1a (MIP-1 alpha) and platelet-derived growth factor-AB (PDGF-AB) in peripheral blood mononuclear cells (PBMC) from 20 persons with either high (n = 10) or low (n = 10) levels of high-density lipoprotein (HDL). PBMC were incubated with 100 ng LPS/ml for up to 160 h, and showed a significantly higher release of the chemokines GRO alpha (P = 0.04) and MIP-1 alpha (P < 0.01) in persons with high HDL, whereas levels of GM-CSF were similar. Levels of EGF, LIF and PDGF-AB were always low, and remained unaltered during 160 h of incubation. These findings indicate that PBMC from persons with high or low levels of HDL have different functional properties, of importance in cell recruitment and activation.
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PMID:LPS-induced release of EGF, GM-CSF, GRO alpha, LIF, MIP-1 alpha and PDGF-AB in PBMC from persons with high or low levels of HDL lipoprotein. 858 Mar 73

The secondary structure in mRNA is essential for many processes, but it can present a technical problem in making full-length cDNA with reverse transcriptases. Furthermore, different reverse transcriptases have differing abilities to transcribe through regions with secondary structure, which can alter the products obtained by reverse-transcribing RNA and then PCR-amplifying the product (RT-PCR). We have been interested in studying the posttranscriptional regulation of epidermal growth factor by RT-PCR and have tested the ability of several reverse transcriptases to reverse transcribe the 3'-untranslated region (3'UTR), a region that contains substantial secondary structure. When low levels of either total RNA or poly(A)+ mRNA were used, we found avian myeloblastosis virus reverse transcriptase (AMV-RT) to be the most robust of all the enzymes tested. Furthermore, contrary to reports that AMV-RT is inhibited by tRNA--which should make it less effective than Moloney murine leukemia virus reverse transcriptase (MMLV-RT) at reverse-transcribing total RNA--adding tRNA to poly(A)+ RNA actually increased the amount of specific RT-PCR product obtained with AMV-RT while it decreased the amount of product and enhanced mispriming with MMLV-RT. We found that pre-incubation of the oligo(dT) primer with total RNA at elevated temperature prior to reverse transcription improved the efficiency of both native and modified MMLV-RTs. These findings support the concept that secondary structures in RNA differentially affect the abilities of different reverse transcriptases to detect transcript diversity and raise the possibility that such structures could affect quantitation using RT-PCR with internal mRNA standards.
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PMID:Secondary structure in the 3' UTR of EGF and the choice of reverse transcriptases affect the detection of message diversity by RT-PCR. 858 21

A series of 36 nitrothiophene tyrphostins were synthesized, 32 of which were novel structures. Their ability to inhibit the epidermal growth factor (EGF) receptor tyrosine kinase was assessed in a cell-free assay. Compounds containing a dinitrile, 2-aminoethene-1, 1-dinitrile or a thioamide group were good inhibitors of the receptor tyrosine kinase. Although anti-proliferative and cytotoxic activity was seen, no evidence of inhibition of EGF receptor autophosphorylation in intact cells was observed. The compounds showed no preferential inhibition of EGF-dependent proliferation of fibroblasts transfected with the EGF receptor. Furthermore, in a panel of squamous cell carcinoma cell lines with varying levels of EGF receptor expression, there was no selective cell kill of lines with the highest EGF receptor expression. The 2-nitro-5-substituted-thiophenes and the 2-nitro-3-substituted-thiophenes showed reduction potentials falling within the range likely to be reduced by cellular reducing agents, while the 2-nitro-4-substituted-thiophenes and 4-nitro-2-substituted-thiophenes did not. Compounds from the 2-nitro-5-substituted-thiophene series were shown to induce DNA damage, while no evidence of DNA damage was demonstrated with compounds from the 2-nitro-4-substituted-thiophene series. The 2-nitro-5-substituted-thiophene compound 4 showed significant tumour-type selectivity in the US National Cancer Institute human tumour cell line panel. The leukaemia cell lines were particularly sensitive to the compound, as were the majority of the colon cancer, melanoma and breast cancer cell lines, while the central nervous system-derived lines and the non-small cell lung cancer lines were particularly resistant. Further work is required to determine the precise mechanisms involved in these effects.
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PMID:Synthesis and biological evaluation of a series of tyrphostins containing nitrothiophene moieties as possible epidermal growth factor receptor tyrosine kinase inhibitors. 867 52

Precursors from the neuroepithelium of the developing cortex and the adult subventricular zone can be cloned in vitro after stimulation with fibroblast growth factor 2 (FGF-2), and they have the potential to give rise to both neurons and glia. The generation of neurons from these clones can be stimulated by either a factor derived from an astrocyte precursor line, Ast-1, or FGF-1. We have shown that neuronal differentiation stimulated by FGF-1 can be inhibited by diacylglycerol lipase inhibitor and mimicked by arachidonic acid, suggesting that the neuronal differentiation is signalled through the phospholipase C gamma pathway. The sequential expression of FGF-2, followed by FGF within the developing forebrain neuroepithelium, fits with the different functions that the two FGFs play in precursor regulation. We have shown that the precursor response to FGF-1 is regulated by a heparan sulphate proteoglycan expressed within the developing neuroepithelium. Precursors restricted to the astrocyte cell lineage can be stimulated by epidermal growth factor or FGF-2F however, the differentiation into glial fibrillary acidic protein-positive astrocytes appears to require a cytokine acting through the leukaemia inhibitory factor-beta receptor.
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PMID:Factors regulating the differentiation of neural precursors in the forebrain. 872 88

Implantation biology is now at a stage where experimental science will be very productive in answering basic questions about the ability of an embryo to implant. The advancement of our knowledge of cytokines and growth factors has been critically important in fuelling the recent new understanding of embryo implantation. Specifically, our increased knowledge of the interleukin (IL)-1 system, as well as leukaemia-inhibiting factor (LIF), epidermal growth factor and colony-stimulating factor-1, and the availability of recombinant protein, specific antibodies and knockout mice, have led to a more detailed outline of implantation events. LIF and IL-1 are the two systems where recent advances have suggested their importance in implantation events. Recently, LIF has been shown in mice to be an endometrial requirement for implantation and embryo development. Although LIF is a pleiotropic molecule, with many interactions in multiple body tissues, in the uterus, concentrations are elevated on day 4 of pregnancy. Experiments with knockout mice have shown the requirement for endometrial LIF for successful implantation. The IL-1 system, consisting of two agonists (IL-1 alpha and IL-1 beta), two receptors (IL-1R types I and II) and the homologous IL-1 receptor antagonist (ra), has also been studied. Knowledge that the embryo secretes IL-1 suggested the interaction between embryonic IL-1 and endometrial receptor, which has been shown to occur. IL-1R type I is plentiful on endometrial epithelial cells and appears to interact with embryonically secreted IL-1 beta to favour implantation. Such implantation events in vivo in mice are blocked by the introduction of large quantities of IL-1ra, consistent with the hypothesis that appropriate interactions between agonist and receptor at the level of the endometrial surface are a requisite for successful implantation. As more specific information on each cytokine or growth factor system comes to light, more complete information on the multiple molecular steps of implantation will become apparent. However, it is clear that no single cytokine or growth factor will be able to explain the complicated events of embryo implantation. Such an important necessary phenomenon has multiple redundancies. The interactions between cytokines and growth factors are becoming increasingly apparent and will need more experimental evidence before a full understanding of implantation is available.
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PMID:Role of embryonic factors in human implantation. 874 98

The regulation of cytokine production by thymic epithelial cells (TEC) in the thymus is under coordinated and temporal control and is important for the development of T cells. Human TEC express TGF-beta R and epidermal growth factor (EGF) receptor, and produce TGF-beta 3 in vitro and in vivo. Furthermore, EGF has been shown to increase IL-1 alpha, IL-1 beta, IL-6 mRNA and protein levels in human TEC. Since EGF has been shown to modulate TGF-beta effector functions, we determined whether TGF-beta can modulate EGF-mediated increases in cytokine gene expression in human TEC. We established that a single TEC expresses both EGF receptor and TGF-beta R. TGF-beta plus EGF synergistically increased leukemia-inhibitory factor (LIF), additively increased IL-6, but had little effect on IL-1 alpha and IL-1 beta mRNA levels. In contrast, TGF-beta alone increased LIF and IL-6, had little effect on IL-1 alpha, and slightly decreased IL-1 beta mRNA levels. The increases in LIF and IL-6 mRNA levels by TGF-beta plus EGF correlate with the increases in LIF and IL-6 concentrations in TEC culture supernatants as detected by ELISA. We also determined the mechanism responsible for the increases in cytokine mRNA levels. TGF-beta plus EGF did not affect transcription of LIF and IL-6 genes; this suggests that the increases in the steady state levels of cytokine mRNA were mediated post-transcriptionally, most likely at the level of mRNA stability. Our data demonstrate that TGF-beta modulates TEC cytokine production. We speculate that TGF-beta produced in situ plays a role in thymocyte development by directly affecting thymocyte differentiation and by indirectly modulating TEC cytokine production.
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PMID:TGF-beta differentially modulates epidermal growth factor-mediated increases in leukemia-inhibitory factor, IL-6, IL-1 alpha, and IL-1 beta in human thymic epithelial cells. 905 4


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