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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical trials of 4-day subrenal capsule assay (SRC assay) were carried out. One hundred and forty-one cases were investigated in order to evaluate the clinical utility of the assay. A total evaluability rate of 81.0% and a response rate of 36.5% were obtained in the SRC assay. The overall predictive accuracy between the tumor sensitivity of the assay and the clinical response was 82.1%. The percentage inhibition of %DNA/protein content of the implanted tumor, as a new predictor of the tumor growth inhibition, also indicated a good prediction rate for the assay. Correlation between the sensitivity test and the end results after chemotherapy in cases of inoperable gastric cancer classified as stage IV was investigated, retrospectively. Comparison of the survival curves between the patients treated with sensitive agents and those with insensitive agents exhibited a significant advantage for the former (p less than 0.01). These results suggest the utility of the SRC assay for clinical use, but histological studies exhibited certain limitations of this assay due to the existence of early host rejection of the implanted tumor. The utility of the SRC assay should be finally evaluated using more histological assessments and clinical trials.
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PMID:[Clinical trials of the subrenal capsule assay]. 361 57

To identify protein tyrosine kinase (PTK) genes preferentially expressed in renal cell carcinoma cell line, we screened a PTK-cDNA-enriched library constructed from RNA of an renal cell carcinoma cell line with a PTK probe, each produced from renal cell carcinoma, gastric cancer or esophageal cancer cell lines by degenerate polymerase chain reaction. Two cDNA fragments of PTK genes, FRK and FLT-3, were isolated from the PTK-cDNA-enriched library of the renal cell carcinoma cell line by differential hybridization technique. The FRK cDNA clone represented 15.8% of the PTK-cDNA-enriched library from the renal cell carcinoma cell line, while the FLT-3 cDNA clone was 2.8% of the same library. Both of the two PTK genes were expressed preferentially in renal cell carcinoma cell lines. This method, described here, is useful for the rapid isolation of PTK cDNA fragments, including a low abundant cDNA, preferentially expressed in a specific cell line.
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PMID:Rapid isolation of cell-type-specific protein tyrosine kinases by degenerate polymerase chain reaction combined with differential hybridization technique. 766 53

The association between genetic instability in repetitive DNA domains and cancer has been reported in different types of malignancies. In this work we perform a comparative study of 29 gastric tumors with paired normal tissue using seven tetra-(FES/FPS, VWA31/A, HTPO, TH01, MBPB) and pentanucleotide (CD4, TP53) STR polymorphic markers regarding loss of heterozygosity and replication error status. Furthermore, we compare the gene frequencies obtained in normal tissue from patients with those of a normal control population from the same area, looking for allele associations between any of these polymorphic loci and gastric cancer risk. The results have shown that FES/FPS and TP53 present the higher rates of somatic instability. The observed results for TP53 are in accordance with those previously reported in gastric carcinogenesis, while instability of FES/FPS is for the first time reported in this tumor type. Our data suggest that different loci show different rates of instability and/or loss of heterozygosity and do not seem to consist of a result of an RER+ phenotype affecting several genomic repetitive domains. Furthermore, the instability in markers TH01, MBPB, TP53, and FES was generally detected in genotypes involving alleles with a high number of repeats. Comparing gene frequencies in patients and normal controls, no significant differences were found, although longer alleles are consistently more frequent in patients for the markers MBPB, TH01, and CD4.
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PMID:Tetra- and pentanucleotide short tandem repeat instability in gastric cancer. 937 35

Highly effective treatment is required for patients with advanced GI cancer. Returning to the starting point for reconsideration of cancer chemotherapy, with the aim of attaining a therapy (self rescuing concept: SRC) with more potential efficacy and less toxicity than current therapy, we report two kinds of chemotherapy in the present paper. They were set up preclinically using the theory of 5-FU biochemical modulation, and demonstrated their usefulness in clinical practice. S-1 is a newly developed oral anti-cancer drug which is a combination of Tegafur (FT), a prodrug of 5-FU and two modulators (CDHP, an inhibitor of 5-FU degradation and Oxo, a selective inhibitor GI toxicity by 5-FU) at a molar ratio of 1:0.4:1. In combination with CDHP, 5-FU gradually released from FT remained longer in plasma, and consequently had high anti-tumor activity, while the combined Oxo significantly suppressed GI toxicity due to 5-FU. The response rate to S-1 of stomach cancer in a phase II study was 46.5% (60/129). Toxicity at more than G3 was less than 10%. In the combination therapy employing 5-FU by CVI (5-FU: 250-350 mg/body for 24 h, 4-6 wks) and low dose consecutive CDDP, CDDP acts mainly as a modulator of 5-FU (to increase 5-FU sensitivity for tumor by inhibition of intracellular Met incorporation). For this purpose, it was found that daily consecutive administration is required, even at low dose of CDDP (3-5 mg/body/day for 5 days). A high response rate (40-60%) was obtained for advanced GI cancer. Toxicity at more than G3 was less than 10%. On the other hand, the possibility has been suggested that so far as 5-FU is concerned, CVI every other day (500-750 mg/body/day for 3 days) is more favorable than long term CVI, with regard to decreasing GI and myelotoxicities based upon the difference in generation time between normal cell (GI mucous membrane and stem cell) and tumor cell cycles. The possibility is suggested that the above-mentioned chemotherapy can become a standard therapy for GI cancer.
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PMID:[Combination therapy of continuous venous infusion (CVI) of 5-FU and low dose consecutive cisplatin (CDDP), and the new oral anti-cancer drug S-1 for advanced gastro-intestinal cancer]. 1009 42

The loss of mismatch repair enzymes increases the mutation rate in microsatellites and coding regions of the genome and appears to be involved in drug resistance. The replication error (RER+) phenotype, associated with microsatellite instability, has been widely described for both familial and sporadic colon cancers and for gastric and endometrial tumors. For ovarian cancer, the incidence of RER+ cases among sporadic tumors is still uncertain. We analyzed epithelial ovarian tumors and ovarian carcinoma cell lines for microsatellite instability and for mutations in the coding regions of different genes, including the recently discovered human CHK-1 gene, which has an important role in controlling cell cycle progression and whose coding region contains a poly(A)9 tract. Microsatellite instability and frameshift mutations in coding regions of BAX, TGFbetaRII, IGFIIR, E2F-4, ICE, and CHK-1 genes were analyzed in ovarian cancer samples and cell lines by polymerase chain reaction (PCR). Approximately 26% of patients showed microsatellite instability in two or more loci. BAT-26 locus showed no alteration in primary tumors. We detected a BAX mutation in one tumor sample and a TGFbetaRII mutation in one cell line. Our findings confirm the presence of the RER+ phenotype in sporadic ovarian cancer. The low rate of mutation in genes previously reported to be altered in colon and gastric cancer suggests that other not yet identified genes might be altered and could play a role in tumor progression and response to treatment in RER+ ovarian tumors.
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PMID:Microsatellite instability and frameshift mutations in genes involved in cell cycle progression or apoptosis in ovarian cancer. 1075 43

We hypothesized that the tolerance for nutrient deprivation as well as angiogenesis might be an important factor for tumor progression under hypovascular conditions. When normal human fibroblasts were subjected to extreme nutrient starvation by culturing in a medium without serum, glucose, and amino acids, cells died within 24 h. When substituted with liver cancer cell lines HepG2, Hep3B, HLE, and HuH-7, cell death occurred within 36 h. In contrast, four of six pancreas cancer cell lines, PANC-1, AsPC-1, BxPC-1, and KP-3, survived for remarkably longer periods; >50% of the cells survived, even after starvation for 48 h. Among three gastric cancer cell lines, MKN28, MKN45, and MKN74, only the most poorly differentiated MKN45 cells survived >36 h. More than 50% of the cells in colon cancer cell lines SW480, WiDr, and DLD-1 survived after 36 h, and the most undifferentiated SW480 cell line survived longest. We examined the possible involvement of PKB/Akt expression in the survival of various cell lines under nutrient starvation conditions. High expression of PKB/Akt was found to be associated with tolerance for nutrient starvation. When Akt antisense RNA expression vectors were introduced into PANC-1 cells, the tolerance was partially but significantly diminished by vectors for Akt1 and Akt2 but not Akt3. Because elimination of the tolerance might serve as a new strategy for cancer therapy, several compounds were tested for this purpose, and troglitazone, an insulin sensitizer, as well as LY294002, a phosphatidylinositol 3-kinase inhibitor, were found to kill PANC-1 cells only under nutrient starvation conditions.
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PMID:Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy. 1108 46

SAP-1 (stomach cancer-associated protein-tyrosine phosphatase-1) is a transmembrane-type protein-tyrosine phosphatase that is abundant in the brain and certain cancer cell lines. With the use of a "substrate-trapping" approach, p130(cas), a major focal adhesion-associated phosphotyrosyl protein, has now been identified as a likely physiological substrate of SAP-1. Expression of recombinant SAP-1 induced the dephosphorylation of p130(cas) as well as that of two other components of the integrin-signaling pathway (focal adhesion kinase and p62(dok)) in intact cells. In contrast, expression of a substrate-trapping mutant of SAP-1 induced the hyperphosphorylation of these proteins, indicating a dominant negative effect of this mutant. Overexpression of SAP-1 induced disruption of the actin-based cytoskeleton as well as inhibited various cellular responses promoted by integrin-mediated cell adhesion, including cell spreading on fibronectin, growth factor-induced activation of extracellular signal-regulated kinase 2, and colony formation. Finally, the enzymatic activity of SAP-1, measured with an immunocomplex phosphatase assay, was substantially increased by cell-cell adhesion. These results suggest that SAP-1, by mediating the dephosphorylation of focal adhesion-associated substrates, negatively regulates integrin-promoted signaling processes and, thus, may contribute to contact inhibition of cell growth and motility.
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PMID:Inhibition of cell growth and spreading by stomach cancer-associated protein-tyrosine phosphatase-1 (SAP-1) through dephosphorylation of p130cas. 1127 35

Our previous comparative genomic hybridization (CGH) study revealed a novel amplified region at 15q26 in two cell lines established from diffuse types of gastric cancer (GC). In this amplified region, FES and IGF1R, known targets on 15q26, were located telomeric to the amplicon in the two cell lines, HSC39 and 40A, suggesting that another tumor-associated gene exists in this region. While screening expressed sequence tags (ESTs) for novel genes in this region, we identified the IQGAP1 amplification. IQGAP1 has been reported to encode a ras GAP-related protein, and its interaction with cadherin and/or beta-catenin induces a dissociation of beta-catenin from the cadherin-catenin complex, one of the mechanisms for cell-cell adhesion. Northern and Western blot analyses revealed that amplification of this gene was accompanied by corresponding increases in mRNA and protein expression. Moreover, immunocytochemical staining showed that overexpressed IQGAP1 accumulated at the membrane, suggesting its colocalization with beta-catenin. Taken together, these findings suggest that IQGAP1 may be one of the target genes in the 15q26 amplicon correlated with a malignant phenotype of gastric cancer cells, such as diffuse and invasive characteristics, through the disruption of E-cadherin-mediated cell-cell adhesion.
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PMID:IQGAP1, a negative regulator of cell-cell adhesion, is upregulated by gene amplification at 15q26 in gastric cancer cell lines HSC39 and 40A. 1128 14

To study host response to CagA, human gastric cancer cell line AGS was infected with a Helicobacter pylori type I wild-type or isogenic cagA-negative mutant. Differentially expressed genes were identified using cDNA array technology. By Northern blotting, downregulation of focal adhesion kinase and upregulation of LIM kinase mRNA in the presence of CagA were clearly verified. Furthermore, upregulation of LIM kinase, macrophage inflammatory protein-2, c-myc, and bone morphogenetic protein-1 and downregulation of transcription factor Y-box binding protein-1 and focal adhesion kinase mRNA in response to H. pylori type I infection compared to the uninfected control could be shown by Northern blotting. Hence, these findings identified new targets for further functional studies on H. pylori-associated pathogenesis.
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PMID:Gene expression profiling in AGS cells stimulated with Helicobacter pylori isogenic strains (cagA positive or cagA negative). 1179 37

Tumor invasion marks a critical point in cancer progression; it is a harbinger of morbidity and mortality. Thus, the cellular events that enable the invasive phenotype are under intense investigation. Epstein-Barr virus (EBV) is associated with a number of cancers, including Burkitt lymphoma (BL) and nasopharyngeal carcinoma (NPC) and is suspected to contribute to their tumorigenesis. On average, 8% of gastric carcinomas have been shown to carry this virus. To explore whether the presence of EBV in gastric carcinoma contributes to tumor progression in this predominantly invasive carcinoma, we examined a panel of 2 in vitro EBV-infected human gastric cancer cell line sublines and their mock-infected AGS parental control line. We found EBV infection caused a marked increase in transmigration of a Matrigel barrier (415% and 303%, p < 0.05, for the 2 infected lines). This correlated with increased motility of these sublines (233% and 140%, p < 0.05). As this pattern of increased motility leading to a more pronounced enhancement of invasion has been noted in other tumor cells, we explored the roles of autocrine signaling pathways previously implicated in carcinoma motility and invasion. Inhibitors to the epidermal growth factor receptor (EGFR) (PD153035), phospholipase C (PLC) (U73122), extracellular-signal regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) (PD089035) and PI-3 kinase (Wortmannin) were not informative. These data suggest that EBV increases migration of AGS cells by a mechanism independent of these autocrine growth factor-induced pathways. Instead, we found that the EBV-infected cells presented increased focal adhesion kinase (FAK) phosphorylation. These findings suggest a role for integrin-mediated signaling in promoting EBV-associated invasiveness.
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PMID:EBV-expressing AGS gastric carcinoma cell sublines present increased motility and invasiveness. 1211 96


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