Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of ionizing radiation on methotrexate (MTX) resistance and gene amplification in cultured mammalian cells was investigated. X-irradiation of mouse EMT-6 cells induced cell killing and MTX resistance due to amplification of dihydrofolate reductase (dhfr) gene in a dose-dependent manner. The highest yields of mutant cells were obtained at approximately D37 (the dose at which 37% of the cells survive), where the frequency of MTX-resistant cells was four- to eightfold over that of the unirradiated population. The proportion of MTX-resistant cells among the survivors increased logarithmically with dose, up to a 1000-fold increase over unirradiated cells at 1000 cGy, the highest dose tested. The induced frequency of MTX resistance after X-irradiation was greater than the induced frequency of 8-azaguanine resistance, which indicates deletion of the hypoxanthine phosphoribosyltransferase gene. Inhibition of poly(ADP-ribose) polymerase by the addition of 3-aminobenzamide before irradiation increased both cell killing and MTX resistance. Metaphase spreads of chromosomes from EMT-6 cells that had been irradiated and subjected to stepwise increases in MTX concentration showed numerous double minutes. Pulsed-field gel electrophoresis of the DNA from cells containing radiation-induced double minutes showed that many copies of the dhfr gene were present on circular DNA molecules of 10(6), 2 x 10(6), and 3 x 10(6) base pairs. These results suggest a relationship between the induction of chromosome aberrations and the induction of gene amplification.
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PMID:X-ray induction of methotrexate resistance due to dhfr gene amplification. 212 27

Treatment of EMT 6 mammary adenocarcinoma cells with Interferon-gamma (IFN-gamma, 10 U.ml-1) plus endotoxin lipopolysaccharide (LPS, 100 ng.ml-1) induces concomitantly a growth arrest and production of citrulline and nitrite from L-arginine. A similar L-arginine-dependent metabolism is responsible for the vascular smooth muscle relaxing effect of stimulated endothelial cells. We therefore investigated the ability of EMT 6 cells to induce the relaxation of endothelium-denuded rat aortic rings precontracted with noradrenaline (1 microM). Pretreatment of EMT 6 cells with IFN-gamma + LPS increased their relaxing potency by 5-10 times. The relaxin effects of control and treated EMT 6 cells were entirely counteracted by NG-monomethyl-L-arginine (300 microM), a specific inhibitor of nitrite and citrulline production from L-arginine, and by methylene blue (10 microM) and LY 83583 (10 microM), two inhibitors of NOo-induced activation of guanylate cyclase. The effect of NG-monomethyl-L-arginine was reversed by L- but not D-arginine (1 mM). It is concluded that IFN-gamma + LPS increase the production of a relaxing factor in EMT 6 cells through the L-arginine-NOo-synthase pathway.
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PMID:Production of an arginine-derived relaxing factor induced by IFN-gamma plus endotoxin in murine adenocarcinoma EMT 6 cells. 212 6

Several studies have examined the synergism of hyperthermia or chemotherapy agents in combination with photodynamic therapy (PDT) to enhance tumor eradication. In our unique approach to treatment, multiple photosensitizers and wavelengths were used: two photosensitizers, Photofrin II and meso-tetra-(4-sulfonatophenyl)-porphine (TPPS4), irradiated at the appropriate therapeutic wavelength for each photosensitizer. EMT-6 mammary tumors were induced in the flanks of BALB/c mice. The mice were assigned to a control group (50 mice) or treatment group (150 mice). All treatment animals and some control animals received photosensitizing drug (5 mg/kg of TPPS4, 5 mg/kg of Photofrin II, or 2.5 mg/kg of both TPPS4 and Photofrin II). All treatment animals and some control animals also received light treatment (630 nm for TPPS4 and/or 658 nm for Photofrin II). The results show that the approach using both drugs and the corresponding therapeutic wavelengths enhanced the effectiveness of PDT. This approach achieved a cure rate of up to 100%, which was, depending on the light intensity used, as much as 40% greater than the rate achieved by the approach using one drug and one wavelength. The results also show that lesser amounts of drug and/or light may be required if both drugs and wavelengths are used, thus lowering the chances of side effects common to PDT. Furthermore, the results indicate that the increased tumor kill is due to a synergistic effect of the two photosensitizers that was tested on the tumor microvasculature in the first few hours after PDT.
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PMID:Use of multiple photosensitizers and wavelengths during photodynamic therapy: a new approach to enhance tumor eradication. 213 4

The roles of secreted and membrane-associated TNFs were investigated in activated macrophage cytolysis of L929, EMT-6, and P815 targets. While all three targets were susceptible to cytolysis in coculture, an anti-TNF antiserum blocked lysis of L929 and EMT-6 but not of the P815 targets. Of the three targets, recombinant human or mouse TNF could only lyse the L929 target; despite the fact that a role for TNF was invoked in lysis of EMT-6 targets in coculture, the latter was strongly resistant to soluble rTNF, even at concentrations 30-40-fold higher than the Ka for its TNF-receptor. Cytolysis of the L929 target occurred when it was cocultured with BCG-activated macrophages even when these effector cells did not secrete TNF, either due to prior chemical crosslinking or to lack of exposure to a triggering level of lipopolysaccharide. Furthermore, by introduction of the anti-TNF antiserum over a dose-range, it was shown that macrophage cytolysis both of L929 and EMT-6 targets occurred in the absence of bioavailable, fluid-phase TNF. Thus, even for targets susceptible to fluid-phase TNF, TNF-dependent, direct macrophage-mediated cytolysis appears to be a function independent of secreted TNF and one that utilizes effector-target contact to express the action of a membrane form of the molecule.
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PMID:Tumoricidal effector mechanisms of murine BCG-activated macrophages: role of TNF in conjugation-dependent and conjugation-independent pathways. 216 18

Tumor necrosis factor (TNF-alpha) is a cytokine produced by macrophages and monocytes, and has been shown to have cytolytic, cytostatic or growth-stimulatory activity on transformed cells. However, the mechanism of these growth modulating activities of TNF-alpha is unknown. By studying the response of different oncogene-transformed NIH3T3 cells to TNF-alpha, we showed that the oncogene v-abl confers resistance to the cytostatic and cytolytic activities on TNF-alpha compared to the parental NIH3T3 cells. Most interestingly, v-abl expression also resulted in a growth-enhancing response to TNF-alpha at up to the highest dose of 6,400 units/ml. These altered properties were not due to the transformation event itself, since EJ-ras oncogene transformed NIH3T3 cells were more susceptible to TNF-alpha than the parental cells. Moreover, EMT-6, a mouse adenocarcinoma cell line, which responded similarly to NIH3T3 cells, did not show growth-enhancement at high TNF-alpha dosages. Though resistant to the direct cytotoxic activity of TNF-alpha, the v-abl transformed cell line was effectively killed by macrophages, as were the other cell lines. This suggests tumor cell killing by macrophages must involve mechanisms in addition to the secretion of TNF-alpha.
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PMID:V-abl confers resistance and growth advantage to TNF-alpha in NIH3T3 cells. 218 46

The Alabama Chapter of the American College of Emergency Physicians is now sponsoring a pilot program using EMT-Basic equipped with semi-automatic ("smart") defibrillators for the treatment of cardiac arrest patients in the field. This article outlines the rationale for the program along with present status of results.
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PMID:The Alabama automated defibrillation pilot program. 223 24

Many controversies exist in prehospital care. The most visible from a physiologic point of view are what is done in the field, how thorough medical accountability should be, and what amount of education is required for EMTs to perform their jobs correctly. The bottom line is good patient care. Such care cannot be achieved without the proper ingredients. These include a knowledgeable EMT, an involved medical director, and community support.
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PMID:Controversies in prehospital care. 229 7

Published reports of out-of-hospital cardiac arrest give widely varying results. The variation in survival rates within each type of system is due, in part, to variation in definitions. To determine other reasons for differences in survival rates, we reviewed published studies conducted from 1967 to 1988 on 39 emergency medical services programs from 29 different locations. These programs could be grouped into five types of prehospital systems based on the personnel who deliver CPR, defibrillation, medications, and endotracheal intubation; the five systems were three types of single-response systems (basic emergency medical technician [EMT], EMT-defibrillation [EMT-D], and paramedic) and two double-response systems (EMT/paramedic and EMT-D/paramedic). Reported discharge rates ranged from 2% to 25% for all cardiac rhythms and from 3% to 33% for ventricular fibrillation. The lowest survival rates occurred in single-response systems and the highest rates in double-response systems, although there was considerable variation within each type of system. Hypothetical survival curves suggest that the ability to resuscitate is a function of time, type, and sequence of therapy. Survival appears to be highest in double-response systems because CPR is started early. We speculate that early CPR permits definitive procedures, including defibrillation, medications, and intubation, to be more effective.
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PMID:Cardiac arrest and resuscitation: a tale of 29 cities. 230 97

The genetic determinant responsible for virulence in Moloney murine leukemia virus (MoMuLV) induced T-cell lymphomagenesis has recently been mapped [J Virol 63:471-480, 1989] by homologous genomic fragment exchange between MoMuLV and MoMuLV-TB to the Clal/Xbal at the 3' end of the genome. This region of MoMuLV and MoMuLV-TB differs in 11 nucleotides. Of these 11 nucleotide differences, 9 are distributed within the two CORE, the two distal NF1, and the two GRE/LVa elements of the enhancer. Since both the CORE binding sites of MoMuLV-TB are mutated with respect to those of MoMuLV, we compared nuclear proteins of a thymus-bone marrow cell line and a T-lymphoma cell line (EMT), which bind to the wild-type and mutant CORE binding sites. Using both the bandshift assay and southwestern analysis with labeled synthetic deoxyoligonucleotides, we showed that a 42-kDa protein from TB and EMT cells bound specifically to the MoMuLV CORE element. The T----C transversion of nucleotide 6 of the CORE consensus, TGTGGT/CTAA, significantly reduced binding of the 42-kDa TB and EMT cell factors. However, the transversion of nucleotide 3 from T----C had little effect on the binding of the 42-kDa protein to the CORE element. In addition, the 42-kDa protein bound weakly to the CCAAT element of MoMuLV. A recombinant virus, NwtTB-6, was generated by introducing the two CORE mutations of MoMuLV-TB into the MoMuLV genome. Although the latency period of NwtTB-6 in the induction of lymphoma was not significantly different from that of MoMuLV, preliminary findings suggest that the lymphoma induced by NwtTB-6 may be more widely distributed.
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PMID:A single mutation in one of the CORE elements of Moloney murine leukemia virus reduced binding of a 42-kDa T lymphoma cell nuclear factor but did not affect lymphomagenesis. 234 87

Radiolabeled fluoromisonidazole (FMISO) is being investigated as an imaging agent for hypoxia in tumors and nonmalignant tissues in myocardial infarct or stroke. In this study in vitro cell cultures were used to characterize the oxygen dependency of FMISO uptake and to examine other modifying factors. The uptake of [3H]FMISO was measured in four cell lines in vitro: V-79, EMT-6(UW), RIF-1, and CaOs-1. The modifying effects of different O2 levels as well as cell growth state and concentration of glucose and nonprotein sulfhydryls were examined. In these cell types an O2 level between 720 and 2300 ppm inhibited FMISO binding by 50%, relative to binding under anoxic conditions. These values bracket the O2 level which confers full radiobiologic hypoxia, about 1000 ppm. Some bound label was released from cells in the first 1 to 3 h after a 3-h anoxic labeling with [3H]FMISO, but this does not represent tritium loss from the parent molecule. Cells from unfed plateau-phase cultures took up less [3H]FMISO than did exponentially growing cells incubated at comparable O2 levels. Reducing glucose to 1/10 or 1/100 of the usual concentration in medium had little effect on binding of micromolar levels of FMISO, except in V-79 cells, where reduced glucose levels were associated with increased FMISO accumulation. Adding cysteamine to the culture medium moderately increased FMISO uptake. We conclude that cell growth state, glucose, and nonprotein sulfhydryl concentrations affect FMISO binding, albeit less than varying O2 levels: anoxic/oxic binding ratios vary from 12.6 to 28 for the four cell types examined. Nonetheless these factors must be considered in evaluating the oxygen-dependent binding of this nitroimidazole in tumors or tissues.
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PMID:Characteristics of the binding of labeled fluoromisonidazole in cells in vitro. 235 84


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