Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activating mutations in the Met receptor tyrosine kinase, both germline and somatic, have been identified in human papillary renal cancer. Here we report a novel germline missense Met mutation, P1009S, in a patient with primary gastric cancer. The dosage of the mutant Met DNA was elevated in the tumor when compared to its matched normal DNA. Therefore, as with hereditary renal papillary cancer, the mutant Met allele may also be selectively duplicated in the tumor. Different from previously reported Met mutations, which occur in the tyrosine kinase domain, this missense mutation is located at the juxtamembrane domain, and is not constitutively activated. However, following treatment with HGF/SF, the P1009S mutant Met protein, expressed in NIH3T3 cells, displays increased and persistent tyrosine phosphorylation compared to the wild-type Met. Importantly, these cells also form colonies in soft agar, and are highly tumorigenic in athymic nude mice. A second nucleotide change in this region of Met, T1010I, was found in a breast cancer biopsy and a large cell lung cancer cell line. Although this previously reported 'polymorphism' did not stimulate NIH3T3 cell growth in soft agar, it was more active than the wild-type Met in the athymic nude mice tumorigenesis assay, suggesting that it may have effects on tumorigenesis. Met has been shown to be highly expressed in human gastric carcinoma cell lines, and our results raise the possibility that activating missense Met mutations could contribute to tumorigenesis of gastric cancer.
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PMID:A novel germ line juxtamembrane Met mutation in human gastric cancer. 1104 81

A survey of cancer treatment in a sample of hospitals > 100 beds conducted in 1998 compared with experience in the US showed that good progress has been achieved in Japan in the screening and early treatment of gastric cancer, and that the prognosis for breast cancer is better than in the West. Although in the past, the cytotoxic therapies available to physicians in Japan vs the West have been different, recent acceleration of regulatory review will result in a convergence of treatment paradigms and some improvement in acute response in many tumour types. However, world wide there is a need for new improved therapies in all cancers evaluated. Particular needs are in the management of NSCLC, advanced disease and cancers which form micrometastases. The eventual hope is that cancer can be turned from a lethal disease into a chronic disease where patients maintain a good QOL. Apart from anti hormonal therapies, the usual approach has been to kill the cancerous cells. However, the new approaches to intervening in the growth and migration of cancerous cells or the host tissue response by molecular targeting offer the promise of achieving a step change in therapy. Although EGF tyrosine Kinase inhibitors such as ZD 1839 have been shown to cause a conventional tumour response in NSCLC, many of these new approaches are unlikely to show a short term response even if they have the capacity to affect tumour development and increase disease free survival. Some compounds will require combination therapy with a conventional cytotoxic or radiotherapy to show their full benefit. For conventional cytotoxics, the usual approach to development has been to select the maximum tolerated dose and then evaluate the efficacy in advanced disease. However, for the new approaches which will not have such severe dose limiting toxicities, it will be necessary to select a surrogate marker of the intended biological effect to select the optimal biological dose (OBD) and dose regimen in phase I/II studies for further evaluation in phase II or III studies which are designed to show the expected patient benefit. The tumour target, the stage of the disease and the possible need for concomitant therapy will also have to be considered according to the mechanism of action of the product.
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PMID:[Development of molecular targeting drugs for the treatment of cancer-therapeutic potential and issues to be addressed in global development]. 1105 19

Adenophora triphylla (AT), an oriental medicinal plant, was extracted using water and several organic solvents and each fraction was assayed for its tumoricidal effects on human Jurkat T cells with 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT). The influence on induction of apoptosis and G1 arrest was also examined. The ethyl acetate fraction showed the most pronounced inhibitory effects on proliferation of Jurkat T cells. Apoptosis was induced in line with up-regulation of FasL, tyrosine phosphorylation and c-fos mRNA levels. Arrest in G1 of the cell cycle was observed in A2780 cells with a wild type p53 gene but not HT-29 cells with a mutant p53 gene. Modifying effects of AT on cell turnover and glutathione(GSH) levels in vivo were also investigated in the stomach of rats given 150 mg/kg of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) by gavage and then fed a diet supplemented with 5% or 1% pulverized AT and 0.5% or 0.2% ethylacetate-extracted AT for 42 hours. The 5% AT and both of the ethylacetate fractions caused significant reduction in proliferating cell nuclear antigen (PCNA)-labeling in the glandular stomach epithelium as compared with the value for the MNNG alone group. In addition, the treatments significantly increased the gastric GSH levels. These results suggest that AT could be a chemopreventive agent against gastric cancer.
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PMID:Suppressive effects of Adenophora triphylla extracts on in vitro tumor cell growth and in vivo gastric epithelial proliferation. 1106 47

Carcinoma of the stomach is one of the most prevalent cancer types in the world today. Two major forms of gastric cancer are distinguished according to their morphological and clinicopathological classifications (well differentiated/intestinal type and poorly differentiated/diffuse type), characteristics that could also be attributed to the altered expression of different types of oncogenes or tumor suppressor genes. Significant differences exist for gastric cancer incidence comparing people of different ethnic origins, implicating various genetic and epigenetic factors for gastric oncogenesis. There are only a limited number of molecular markers available for gastric cancer detection and prognostic evaluation, among which are tyrosine kinases. There is convincing evidence that tyrosine kinases are involved in oncogenesis and disease progression for many human cancers. Amplifications of certain tyrosine kinases (c-met, k-sam and erbB2/neu) have been associated with human gastric cancer progression. Alternatively spliced transcripts and enhanced protein-expression levels for some of these tyrosine kinases are correlated with clinical outcomes for gastric cancer patients. With advent of high throughput techniques, it is now possible to detect nearly all expressed tyrosine kinases in a single screen. This increases the chance to identify additional tyrosine kinases as predictive markers for gastric cancers. In this article, we will first review the literature data concerning certain tyrosine kinases implicated in gastric carcinogenesis and then summarize more recent work which provide comprehensive tyrosine kinase profiles for gastric cancer specimens and cell lines. Two new gastric cancer molecular markers (tie-1 and mkk4) have been identified through the use of these profiles and demonstrated effective as clinical prognostic indicators.
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PMID:Tyrosine kinases and gastric cancer. 1111 48

Contact-dependent activation of the cag organelle, a type IV secretion system of Helicobacter pylori, promotes translocation of CagA into the host cell. CagA is an immunodominant antigen of H. pylori, encoded by cag. It is thought to be associated with severe clinical outcomes, but has an unclear role in pathogenesis. Now we know that CagA is injected into the host and is tyrosine-phosphorylated by a membrane-associated eukaryotic tyrosine kinase. After activation, CagA induces morphological changes in the host, as well as actin reorganization, variations in the cell cycle and autocrine effects. Subversion of cell control may ultimately lead to cellular damage and to increased risks for gastric cancer development. cag instability contributes to long-term persistence within the host by attenuating bacterial virulence. We still do not know if additional factors are co-translocated with CagA and we do not know their specific mechanisms of action, but there is a strong experimental evidence that indicates that cag is the major player in the host-pathogen relationship.
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PMID:Cellular responses induced after contact with Helicobacter pylori. 1117 32

Activation of proteases can play an important role in apoptotic cell death induced by anticancer drugs. To assess involvement of activation of cysteine and serine proteases in anticancer drug-induced apoptosis, we tested effect of inhibitors of cysteine and serine proteases on sensitivity to anticancer drugs in MKN45 gastric cancer cells. Cytotoxic effect by adriamycin (ADM), SN-38 (active form of irrinotecan) and cisplatin (CDDP) was significantly prevented by cotreatment with Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk) (p<0.01), a pancaspase inhibitor compared with drug alone using MTT assay. In contrast, cotreatment with N-acetyl-Tyr-Val-Ala-Asp aldehyde (AC-YVAD-CHO), a caspase 1 inhibitor did not prevent any cytotoxic effect of these drugs. Cotreatment of N-acetyl-Asp-Glu-Val-Asp aldehyde (AC-DEVD-CHO), a caspase 3 inhibitor prevented cytotoxic effect of VP-16 and SN-38 (p<0.01). Prevention of these cytotoxic effects by caspase inhibitors was not dose-dependent. Cotreatment of N-tosyl-L-lysyl chloromethylketone (TLCK), a serine protease inhibitor significantly prevented cytotoxic effect of ADM, SN-38, 5-fluorouracil (5-FU) and CDDP in a slight dose-dependent manner (p<0.01) except for etoposide (VP-16) and docetaxel (TXT), while an other serine protease inhibitor, N-tosyl-L-phenylalanyl chloromethylketone (TPCK) did not prevent any anticancer drug-induced cytotoxic effect. These effects were associated with prevention of internucleosomal DNA ladder formation in apoptosis. Further, protease inhibitors did not block induction of cytochrome c, that can explain the partial effect of prevention by anticancer-induced cell death. These results suggest that anticancer drug-induced cytotoxic effect is mediated by activation of serine protease (caspase-independent) as well as caspase-dependent pathway leading to apoptotic cell death, and that protease-independent pathway may also be involved in apoptotic pathways. The involvement of protease in signal transduction pathways may differ in cytotoxic action of drugs in gastric cancer cells.
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PMID:Effect of inhibitors of cysteine and serine proteases in anticancer drug-induced apoptosis in gastric cancer cells. 1135 Dec 55

The action of peroxynitrite in vivo has been proposed to account for the involvement of nitrotyrosine in the pathogenesis of many diseases. However, it has been demonstrated that nitrite under acidic conditions, similar to those in the human stomach, also has the ability to nitrate tyrosine. Dietary nitrate is also implicated in the progression of gastritis and gastric cancer and elevated levels of nitrate are found in many disease states in which nitrotyrosine may play a role. Thus, we investigated whether the dietary nitrate intake might contribute towards the plasma protein-bound levels of nitrotyrosine. Seven healthy, non-smokers participated in a two-day study consisting of a nitrate-low control day followed by a day during which three nitrate-rich meals were consumed. Maximal urinary excretion was attained 4-6 hours after consumption of a meal and the maximum was proportional to the dose. Plasma nitrate was elevated nine-fold, 1 hour after consumption of a meal containing 128.3 mg nitrate. Plasma nitrated protein levels did not appear to alter significantly from basal 1 hour after supplementation with a nitrate-rich meal. Thus dietary nitrate does not appear to contribute to the levels of plasma nitrated proteins, as determined using a competitive inhibition of binding ELISA assay, but this does not preclude any contribution it may make to the total body burden of nitrotyrosine.
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PMID:Lack of influence of dietary nitrate/nitrite on plasma nitrotyrosine levels measured using a competitive inhibition of binding ELISA assay. 1169 34

Opposite biological effects of arsenic trioxide (As(2)O(3)) and arsacetin on the growth of human gastric cancer MGC-803 cells have been observed. Results show that As(2)O(3) inhibited the growth of MGC-803 cells by triggering apoptosis, whereas arsacetin promoted the cell proliferation and seemed to stimulate the secretion of some growth factors at the same micromolar concentrations. Further studies showed that As(2)O(3) could regulate protein tyrosine kinase activity, protein tyrosine phosphorylation, and Bcl-2 protein and upregulate p53 protein. The ability of arsacetin to promote cell proliferation is linked with causing the opposite effects on these factors. These results indicate that the opposite biological effects of As(2)O(3) and arsacetin involve different regulations of molecular mechanisms in MGC-803 cells and that arsacetin may be a potential tumor promoter.
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PMID:Opposite biological effects of arsenic trioxide and arsacetin involve a different regulation of signaling in human gastric cancer MGC-803 cells. 1183 93

The PTEN tumor suppressor gene on 10q23.3, responsible for the Cowden and Bannayan-Zonana syndromes, encodes a dual-specificity phosphatase able to dephosphorylate both tyrosine phosphate and serine/threonine phosphate residues. Mutational inactivation of PTEN has been reported in various malignancies, including endometrial cancers, ovarian cancers, and glioblastomas. In this study, we investigated PTEN gene mutations in 10 gastric cancer cell lines and 58 primary gastric cancers by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP). Hypermethylation of promoter region CpG islands, an alternative mechanism of gene inactivation to coding region mutations, was also evaluated by methylation specific PCR (MSP). Only one (1.7%) of the 58 primary tumors carried a somatic 5-bp deletion in intron 7 of PTEN, which did not alter the mRNA sequence, and no mutations were detected in any of the cell lines. Similar levels of PTEN mRNA expression were observed in all cell lines and primary tumors studied by RT-PCR, and PTEN promoter CpG islands remained unmethylated. Therefore, we conclude that PTEN does not participate in gastric carcinogenesis as a tumor suppressor gene.
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PMID:Analysis of genetic and epigenetic alterations of the PTEN gene in gastric cancer. 1196 46

GIPC1/GIPC/RGS19IP1, GIPC2, and GIPC3 genes constitute the human GIPC gene family. GIPC1 and GIPC2 show 62.0% total-amino-acid identity. GIPC1 and GIPC3 show 59.9% total-amino-acid identity. GIPC2 and GIPC3 show 55.3% total-amino-acid identity. GIPCs are proteins with central PDZ domain and GIPC homology (GH1 and GH2) domains. PDZ, GH1, and GH2 domains are conserved among human GIPCs, Xenopus GIPC/Kermit, and Drosophila GIPC/ LP09416. Bioinformatics revealed that GIPC genes are linked to prostanoid receptor genes and DNAJB genes in the human genome as follows: GIPC1 gene is linked to prostaglandin E receptor 1 (PTGER1) gene and DNAJB1 gene in human chromosome 19p13.2-p13.1 region; GIPC2 gene to prostaglandin F receptor (PTGFR) gene and DNAJB4 gene in human chromosome 1p31.1-p22.3 region; GIPC3 gene to thromboxane A2 receptor (TBXA2R) gene in human chromosome 19p13.3 region. GIPC1 and GIPC2 mRNAs are expressed together in OKAJIMA, TMK1, MKN45 and KATO-III cells derived from diffuse-type of gastric cancer, and are up-regulated in several cases of primary gastric cancer. PDZ domain of GIPC family proteins interact with Frizzled-3 (FZD3) class of WNT receptor, insulin-like growth factor-I (IGF1) receptor, receptor tyrosine kinase TrkA, TGF-beta type III receptor (TGF-beta RIII), integrin alpha6A subunit, transmembrane glycoprotein 5T4, and RGS19/RGS-GAIP. Because RGS19 is a member of the RGS family that regulate heterotrimeric G-protein signaling, GIPCs might be scaffold proteins linking heterotrimeric G-proteins to seven-transmembrane-type WNT receptor or to receptor tyrosine kinases. Therefore, GIPC1, GIPC2 and GIPC3 might play key roles in carcinogenesis and embryogenesis through modulation of growth factor signaling and cell adhesion.
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PMID:GIPC gene family (Review). 1201 74


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