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 mechanism(s) with which tumor target cells actively resist the lethal lesion induced by murine macrophage cytolytic factory (CF) has been probed by drug-induced sensitization of these cells. We have examined whether drug-induced sensitization is attributable to the action of these drugs on cellular DNA, RNA, or protein synthetic rates. The murine mammary adenocarcinoma cell line EMT-6 pretreated with a dose range of actinomycin-D (.03-3.0 micrograms/ml) for 4 hr was inhibited from 66 to 98% in DNA synthesis rate, from 81 to 93% in RNA synthesis rate, and from 38 to 52% in protein synthesis rate. The maximum sensitization toward lysis by CF was achieved with a drug dose of 1.0 micrograms/ml. The lack of correlation between the drug-induced effects on sensitization and effects on these metabolic rates was evident from the correlation coefficients for the percentage of maximum sensitization of the target toward CF-induced lysis, and the percent of inhibition of DNA, RNA, and protein synthesis. These were 0.11, -0.11, -0.44, respectively. Similarly, target cells treated with a dose range of cycloheximide (0.3-30 micrograms/ml) were inhibited from 81 to 95% in DNA synthesis rate, 68 to 81% in RNA synthesis rate, and 82 to 93% in protein synthesis rate. However, at none of the drug levels employed was significant sensitization of the target cell to CF-induced lysis observed. This was reflected in the correlation coefficients of -0.55, -0.28, and -0.34 for DNA, RNA, and protein synthetic rates, respectively. The essential role of cellular microtubule-dependent events early in the lytic mechanism was demonstrated by exposing colchicone-treated targets to CF. While colchicone could markedly inhibit lysis if introduced before CF, this inhibitory effect was not detected if the drug were withheld for 4 hr after CF exposure. The importance of the repair mechanism(s) early in the cellular response to lesion formation was demonstrated by altering the schedule for CF and actinomycin D administration to the target. If actinomycin D treatment was withheld from the targets for as little as 3 hr following introduction of CF, the lytic mechanism had already bypassed the drug-sensitive steps, manifest in markedly decreased susceptibility to lysis. Collectively, the data show that the ability of the EMT-6 target cells to resist CF-induced lysis does not depend solely on the ability of the cells to synthesize DNA, RNA, or protein.
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PMID:Sensitization of tumor target cells to cytolysis by murine macrophage cytolytic factor by drugs inhibiting DNA, RNA, and protein synthesis. 346 37

Subrenal capsule assay (SRC assay) was investigated to evaluate the usefulness as an in vivo chemosensitivity test of anticancer agents. The pathological study on the growth of the implanted tumor and host response indicated that the assay had to be done by four-day assay. The analysis of the isotope incorporation into the implanted tumor supported this results. As determination of tumor sensitivity by the microscopic measurement showed the large standard deviation, the DNA and protein content was determined for the evaluation of sensitivity by percent inhibition of the DNA/protein content (%DNA/protein). Ninety five fresh tumor specimens were examined and evaluated by relative variation of the calculated tumor weight (delta TW/TW0), while 64 specimens by %DNA/protein. The evaluability rates using delta TW/TW0 and %DNA/protein were 84.2% and 87.5%, respectively. All over predictive accuracy between the clinical responses and the results of the assay evaluated by delta TW/TW0 was 78.6%, while 81.8% was obtained by %DNA/protein. From these results, the potential utility of SRC assay examined on 4 day for determining chemosensitivity by %DNA/protein seems to be beneficial for clinical use.
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PMID:[Experimental and clinical studies on subrenal capsule assay for predicting individual tumor chemosensitivity]. 357 73

Experiments were designed to measure cross-link formation following combined treatment of EMT-6/Ro tumor cells with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and misonidazole (MISO) in vitro. To avoid MISO-induced glutathione (GSH) depletion, which might contribute to enhanced monoadduct formation by reducing the protective GSH pools, a post-incubation (i.e. treatment with CCNU for one hour in air followed by MISO treatment in hypoxia) protocol was adopted. Utilizing this treatment scheme, it was possible to significantly enhance CCNU toxicity by post-treating with MISO immediately after exposure to CCNU. Enhanced cross-link formation detected by alkaline elution, at this time, correlated well with the magnitude of cell-kill enhancement, thereby implicating enhanced cross-link formation in the mechanism of potentiation. However, if the cells were allowed to incubate for various intervals between CCNU and MISO treatments, the magnitude of potentiation progressively diminished. Beyond approximately 8-10 hours (corresponding to the time required for maximal cross-link formation after CCNU treatment), treatment with MISO was ineffective at potentiating CCNU cytotoxicity. These experiments suggest that chemopotentiation can be produced by treating with MISO after treatment with CCNU (post-incubation) and that enhanced cross-link formation is involved in the mechanism of MISO chemopotentiation of CCNU activity. The kinetic studies, using the post-incubation protocol, further suggest that the chemopotentiating effect of MISO is exerted subsequent to monoadduct formation and probably does not involve inhibition of DNA-DNA cross-link repair.
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PMID:Cross-link formation and chemopotentiation of EMT-6/Ro cells exposed to MISO after CCNU treatment in vitro. 375 61

A growth regulatory factor, which reversibly inhibits DNA synthesis and proliferation of fibroblasts, has been isolated from medium conditioned by exposure to density-inhibited mouse 3T3 cells. This factor, termed FGR-s (13K), yielded a single polypeptide (Mr 13,000) when analyzed by SDS PAGE under both reducing and nonreducing conditions. The dose-response curve of growth inhibition by FGR-s (13K) showed that 50% inhibition of 3T3 cell proliferation was achieved at a concentration of approximately 3 ng/ml, corresponding to approximately 0.23 nM. The activity of FGR-s (13K) was depleted by passing the material over an affinity column containing the monoclonal antibody 2A4; this monoclonal antibody had been previously characterized to bind to the Mr 13,000 polypeptide. These results indicate that we have purified a growth regulatory factor that acts to inhibit the proliferation of cells in an autocrine pathway.
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PMID:Growth control in cultured 3T3 fibroblasts. V. Purification of an Mr 13,000 polypeptide responsible for growth inhibitory activity. 394 88

The effect of high specific activity thymidme-(3)H on proliferation and antibody production, using the hemolytic plaque-forming technique, by spleen cell suspensions in vitro from rabbits killed after a boost of SRC's has been studied. High specific activity thymidine-(3)H inhibited the proliferative ay well as the antibody response to antigen, and it was conduded that this was the result of the incorporation of radioactive (3)H into the nuclei of dividing cells which were synthesizing antibody in these cultures. The stimulation of the rate of DNA synthesis by specific antigen could be correlated with the ability of antigen to maintain antibody production, as measured by the specific hemolytic plaque-forming technique, above levels found in control cultures, incubated without antigen. Radioautographic studies of PFC's in vitro showed that the majority of the cells arose from the DNA-synthesizing population of cells in these cultures, confirming the conclusions from the results of the inhibitory effects of high specific-activity thymidine-(3)H on PFC's. It was found that these PFC's, labeling with thymidine-(14)C, formed only a small proportion of all the cells labeled in this way in these cultures. The postulation was made that antigen, in vitro, provided a stimulation for cell proliferation in the responsive population of rabbit spleen cells, but that only a small proportion of this population could be induced by antigen to synthesize antibody.
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PMID:Antibody production in vitro. I. Single cell studies of the secondary response to sheep erythrocytes. 564 63

EMT-6/UW tumours were treated in vivo with X-rays, cyclophosphamide, or bleomycin. Cell survival was assayed in vitro following tumour disaggregation with trypsin or an enzyme cocktail (EC) consisting of pronase, collagenase and DNase which gives a 10-20 x higher cell yield. Surviving fraction was lower after cyclophosphamide treatment for cells isolated with EC than for cells prepared with trypsin. The opposite result was obtained with bleomycin; trypsin-isolated cells appeared more sensitive. In attempting to determine the basis for this discrepancy, it was found that both dissociation methods isolate a non-representative cell sample with fewer cells in DNA synthesis (12-13%) than in the original tumour (approximately 22%). The specific nature of the interaction between the injury caused by drug and enzyme remains to be elucidated.
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PMID:Response of an in vivo-in vitro tumour to X-rays and cytotoxic drugs: effect of tumour disaggregation method on cell survival. 615 76

Ionizing radiation inhibited the development of specific haemolysin-producing cells (PFC) and depressed the incorporation of (3H) thymidine by rabbit spleen explants responding to SRC in the culture medium. In contrast to these effects, the rates of incorporation of precursors for protein and RNA synthesis were much less affected. The depression of (3H) thymidine incorporation was found to result from a quantitative reduction of new DNA synthesis, without any change in the proportion of labelled cells, at any time after irradiation. The DNA synthesis occurring in these cells preparing to develop antibody-producing capacity was thus radio-sensitive, but the exact nature of the defect resulting from exposure to radiation requires further study.
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PMID:The acute effects of ionizing radiation on DNA synthesis and the development of antibody-producing cells. 617 68

Bacteriophage lambda structural head protein D has physiochemical properties in common with eukaryotic chromosomal proteins. It has a low affinity for hydroxylapatite, it is heat stable and acid soluble. Moreover, it cross-reacts immunologically with histones H2A and H2B. The deduced primary structure of the D protein shows striking homology to calf chromosomal high mobility group HMG-14 protein. There are two clusters of four ( LSAK , ASDE ) and one of three (APA) identical amino acid residues. Additionally the cluster ETK of protein D occurs three times in HMG-14 and 14 single identical residues are present. A mechanism for an alternative to a nucleosomal mode of nuclear DNA condensation and a possible function of HMG proteins are discussed.
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PMID:The head protein D of bacterial virus lambda is related to eukaryotic chromosomal proteins. 623 40

Conditioned supernatants (CS) obtained from activated murine peritoneal macrophages inhibit tumor cell mitochondrial respiration. EMT-6 cells exposed to CS were markedly inhibited in their ability to oxidize succinate (11.8 ng-atoms 02/min/10(6) cells base line; 3.2 CS treated), malate (15.4 base line, 3.6 CS treated), and tetramethylphenylenediamine (27.6 base line, 10.6 CS treated). The CS was also found to inhibit DNA synthesis in EMT-6 cells (98.9% inhibition of [3H]thymidine incorporation), but did not cause cell lysis. Mitochondrial respiration inhibition activity was not detected in CS until 4 hr; it reached a maximum at 18 hr and declined rapidly by 24 hr. EMT-6 cells recovered from inhibition if the CS was removed from culture, but no recovery was observed if the target cells were in continuous exposure to CS for 72 hr. Fractionation of CS by using a molecular exclusion column of Sephacryl S-200 resulted in the recovery of two peaks that showed respiration inhibitory activity. These peaks, eluting at 55,000 and 80,000 daltons, mediated the inhibition of malate and succinate oxidation and were cytostatic for EMT-6 cells.
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PMID:Activated macrophages secrete a soluble factor that inhibits mitochondrial respiration of tumor cells. 648 Nov 63

Examined by flow cytofluorometric analysis, the DNA distribution of EMT 6 tumor cells was highly perturbed after one hour of in vitro incubation with: RPCNU, RFCNU, chlorozotocin (CZT) or 185 (CNCC), four new nitrosourea derivatives. After the treatment with chlorozotocin (20 micrograms/ml) and CNCC (50 micrograms/ml), most of cells were in G2 + M phase and this accumulation lasted more than 48 hours without any restoration before 72 hours. RPCNU (20 micrograms/ml) and RFCNU (50 and 65 micrograms/ml) induced and accumulation of cells in G2 + M phase during 24 hours. The normal state was regained after 48 hours. These reduced rate of progression of the cells through S phase and the G2 block observed after exposure to the new compounds, should, in part, explain their antitumoral activity.
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PMID:Flow cytofluorometric analysis of the effects of new nitrosourea derivatives on proliferation of EMT 6 tumor cells "in vitro". 701 9


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