Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamate, an excitatory neurotransmitter, is neurotoxic at high concentrations. Neuroglial cells, including astrocytes and microglia, play an important role in regulating its extracellular levels. Cultured human monocytic THP-1 cells increased their glutamate secretion following 18 and 68 h exposure to the inflammatory mediators zymosan, phorbol myristate acetate (PMA), lipopolysaccharide, interferon-gamma, tumor-necrosis factor-alpha and interleukin-1beta. Cultured astrocytoma U-373 MG cells increased their glutamate secretion following similar exposure to zymosan and PMA. DL-Alpha-aminopimelic acid, an inhibitor of the glutamate secretion system, reduced extracellular glutamate in both cell culture systems, while the high-affinity glutamate uptake inhibitors D-Aspartic acid, DL-threo-beta-hydroxyaspartic acid and L-trans-pyrrolidine-2,4-dicarboxylic acid increased extracellular glutamate in U-373 MG, but not THP-1 cell cultures. In co-cultures of THP-1 and U-373 MG cells, extracellular glutamate levels were increased significantly by the Alzheimer beta-amyloid peptide (1-40) and were decreased significantly by the anti-inflammatory drug dexamethasone. These data indicate that inflammatory stimuli may increase extracellular glutamate while antiinflammatory drugs decrease it.
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PMID:Regulation of glutamate in cultures of human monocytic THP-1 and astrocytoma U-373 MG cells. 930 40

The integrin alpha(v)beta3 interacts with the arginine-glycine-aspartic acid (RGD) tripeptide recognition sequence of a variety of extracellular matrix proteins. Recent studies show that alpha(v)beta3 plays an important role in tumor-induced angiogenesis and tumor growth and that antagonists of alpha(v)beta3 inhibit angiogenic processes that include endothelial cell adhesion and migration. Consequently, we reasoned that an RGD-based peptidomimetic antagonist of alpha(v)beta3 might inhibit tumor angiogenesis and tumor growth in vivo. An RGD-peptidomimetic library was screened to identify antagonists of vitronectin binding to alpha(v)beta3, and the compounds chosen were modified to produce selective and potent inhibitors of alpha(v)beta3. One of these compounds, beta-[[2-2-[[[3-[(aminoiminomethyl)amino]-phenyl]carbonyl]amino]ac etyl]amino]-3,5-dichlorobenzenepropanoic acid (SC-68448), inhibited vitronectin binding to both alpha(v)beta3 and the closely related platelet receptor, alpha(IIb)beta3, in a dose-responsive manner. SC-68448 inhibited vitronectin binding to alpha(v)beta3 (IC50, 1 nM) and fibrinogen binding to the platelet receptor alpha(IIb)beta3 (IC50, >100 nM), demonstrating that SC-68448 was 100-fold more potent as an inhibitor of alpha(v)beta3 versus alpha(IIb)beta3. In cell-based studies, SC-68448 inhibited alpha(v)beta3-mediated endothelial cell proliferation in a dose-dependent manner but did not inhibit tumor cell proliferation, suggesting that effects on endothelial cell proliferation were not due to SC-68448-induced cytotoxicity. In accord with these results, SC-68448 inhibited angiogenesis in vivo in a basic fibroblast growth factor-induced rat corneal neovascularization model. A xenogeneic severe combined immune deficiency mouse/rat Leydig cell tumor model was developed for testing SC-68448 as an inhibitor of tumor growth in vivo. Rat Leydig cell tumors grew rapidly in severe combined immune deficiency mice and produced humoral hypercalcemia of malignancy. SC-68448 inhibited the growth of the tumors in mice by up to 80% and completely blocked the development of hypercalcemia. Together, these results demonstrate the feasibility of antitumor therapies based upon the development of nontoxic small molecule pharmacological antagonists of integrin alpha(v)beta3.
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PMID:A peptidomimetic antagonist of the integrin alpha(v)beta3 inhibits Leydig cell tumor growth and the development of hypercalcemia of malignancy. 958 35

Patients who develop squamous cell carcinoma of the head and neck (SCCHN) are often malnourished because of poor dietary habits, excessive alcohol consumption, local tumor effects, tumor-induced cachexia, and the effects of various therapies. The composition of the diet may be a risk factor for the development of head and neck cancer as well as tumor progression. This study compares the amino acid profiles in the banked serum of patients with and without SCCHN. In comparison to the control group, patients with SCCHN had significantly decreased preoperative serum levels of alanine (p = 0.006), asparagine (p = 0.002), aspartic acid (p = 0.0001), glycine (p = 0.0002), histidine (p = 0.002), 3-methylhistidine (p = 0.001), ornithine (p = 0.001), phenylalanine (p = 0.002), serine (p = 0.002), taurine (p < 0.0001), and threonine (p = 0.001). Levels of cystine were significantly elevated in the group of cancer patients (p < 0.0001). No significant differences were noted on the basis of T stage, N stage, or nutritional status. Serum levels increased postoperatively for the majority of the amino acids tested. Postoperative histidine levels were associated with tumor recurrence (p = 0.04). Serum amino acid levels may prove to be useful markers of disease status and provide prognostic information.
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PMID:Altered serum amino acid profiles in head and neck cancer. 958 33

Germ-line mutations in a serine/threonine kinase gene, LKB1, were recently shown to underlie Peutz-Jeghers syndrome (PJS), a hereditary disorder that predisposes to benign and malignant tumors of multiple organ systems. Most mutations that have been described thus far dramatically change the predicted protein and are likely to be of an inactivating nature. This observation and a previous observation that the LKB1 locus is often deleted in PJS polyps suggest that the gene may function as a tumor suppressor. We examined whether somatic mutations in this gene are present in sporadic carcinomas of the colon and testis, tumors that are characteristic of PJS. First, 20 randomly selected colorectal and 28 testicular tumors were analyzed by single-strand conformation polymorphism analysis. No mutations in LKB1 were found in colorectal tumors. One testicular tumor displayed a heterozygous missense type variant, in which glycine 163 was changed to aspartic acid. This change was absent in the DNA of normal tissue. To better focus our efforts, we tested 75 additional colon carcinomas for loss of heterozygosity at 19p, where LKB1 is localized. Of 75 samples analyzed, 50 were informative with a closely linked marker, D19S886, and 13 (26%) of these displayed loss of heterozygosity. The 13 tumors were scrutinized for LKB1 mutations by genomic sequencing. This analysis revealed no changes. Together, these findings suggest that somatic mutations of LKB1 are not frequent in colorectal and testicular cancer.
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PMID:Somatic mutations in LKB1 are rare in sporadic colorectal and testicular tumors. 960 48

Beta-catenin plays essential roles in both intercellular adhesion and signal transduction. As a signaling molecule, beta-catenin supplies an activating domain to the T-cell factor/lymphoid enhancer-binding factor family of DNA-binding proteins and activates gene transcription. Posttranslational stabilization of beta-catenin, leading to elevated protein levels and constitutive gene activation, has been proposed as an important step in oncogenesis. Stabilization of beta-catenin can occur through mutation to highly conserved amino acids encoded in exon 3 of the beta-catenin gene (CTNNB1). To determine whether this pathway of malignant transformation is important in prostate cancer, we analyzed 104 prostate cancer tissue specimens, 4 prostate cancer cell lines, and 3 prostate tumor xenografts for activating mutations in exon 3 of CTNNB1. Mutations were detected in 5 of the 104 prostate cancer tissue samples. Four of the five mutations involved serine or threonine residues implicated in the degradation of beta-catenin. A fifth tumor had a mutation at codon 32, changing a highly conserved aspartic acid to a tyrosine. Mutational analysis of multiple regions from several tumor samples showed that the beta-catenin mutations were present focally and therefore may occur during tumor progression.
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PMID:Beta-catenin mutations in human prostate cancer. 963 71

An anticancer drug adriamycin (ADR) was incorporated into polymeric micelles forming from poly(ethylene glycol)-poly(aspartic acid) block copolymer by chemical conjugation and physical entrapment. Structural stability of the polymeric micelles was found to be dependent on both the contents of chemically conjugated and physically entrapped ADR. The polymeric micelle with high contents of the chemically conjugated ADR and the physically entrapped ADR expressed very high in vivo antitumor activity against murine C 26 tumor, while the polymeric micelle with only the chemically conjugated ADR showed negligible in vivo activity. This indicates that the physically entrapped ADR played a major role in antitumor activity in vivo. For the polymeric micelle with the high ADR contents, it was found that a dimer of adriamycin molecules formed and that this dimer was physically entrapped in the inner core of the micelle as well as intact ADR.
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PMID:Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor. 968 75

The current study examined sera from 160 colon cancer patients and 60 normal individuals to determine whether antibody to mutated p21 ras protein was present. Studies focused on the aspartic acid substitution at amino acid position 12 (denoted D12), one of the most common mutations in colon adenocarcinoma. IgA antibodies directed against mutated p21 ras-D12 protein were detected in 51 (32%) of 160 colon cancer patients, but only in 1 (2.5%) of 40 normal individuals. The greater incidence of antibody in cancer patients provides presumptive evidence that immunization to the ras proteins occurred as a result of the malignancy. Examination of sera for antibody reactivity to wild-type p21 ras protein (denoted p21 ras-G12) as well as p21 ras proteins bearing the D12, V12, S12, or L61 mutations showed that antibody detected was largely to normal segments of the p21 ras protein. Epitope mapping, using peptide neutralization assays with mutated or normal ras peptides as competitors, demonstrated that in 10 (67%) of 15 sera examined the antibody reactivity to p21 ras-G12 protein was neutralized by peptides near the carboxyl terminus of p21 ras protein, but not by peptides spanning the specific point mutation region. Antibody reactivities correlated with peripheral blood lymphocyte count, but did not correlate with patient age, sex, histology, stage, tumor locus, lymph node metastasis, or serum carcinoembryonic antigen.
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PMID:Antibody to ras proteins in patients with colon cancer. 981 96

The MDM2 oncogene product is a regulator of the p53 tumor suppressor. MDM2 is cleaved by Caspase 3 (CPP32) during apoptosis after aspartic acid-361, generating a 60 kd fragment. Here we report that human tumor cell lines often express high levels of a 60 kd MDM2 isoform (p60) in the absence of apoptosis. We demonstrate that p60 is a product of caspase cleavage of full length MDM2 after residue 361. The protease that cleaves MDM2 in non-apoptotic cells appears to be distinct from the apoptosis-specific Caspase 3, since Caspase 3 substrate poly(ADP-ribose) polymerase (PARP) is not cleaved in cells producing p60. The p60 form of MDM2 is a significant fraction of the p53-bound MDM2 protein in certain tumor cells, suggesting that it functions in the regulation of p53. p60 is also detected in breast tumors overexpressing MDM2. These observations suggest that MDM2 is regulated by caspase processing in non-apoptotic cells, and may account for the MDM2 proteins of similar mobility seen in tumors and other cell lines.
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PMID:A 60 kd MDM2 isoform is produced by caspase cleavage in non-apoptotic tumor cells. 984 Sep 26

SV40 large tumor-antigen (T-ag) nuclear import is enhanced by the protein kinase CK2 (CK2) site (Ser111Ser112) flanking the nuclear localization sequence (NLS). Here we use site-directed mutagenesis to examine the influence of negative charge and conformation at the site on T-ag nuclear import and recognition by the NLS-binding importin subunits. Negative charge through aspartic acid in place of Ser111 simulated CK2 phosphorylation in enhancing nuclear accumulation to levels well above those of proteins lacking a functional CK2 site. This was shown to be through enhancement of T-ag NLS recognition by importin using an ELISA-based assay. Asp112-substituted mutants containing proline at positions 109, 110 (wild-type position) or 111 were compared to assess the role of conformation at the CK2 site. Maximal nuclear import of the protein with Pro109 was lower than that of the Pro110 derivative, with the Pro111 variant even lower, these differences also being attributable to effects on importin binding. All results indicate a correlation of the initial nuclear import rate with the importin binding affinity, demonstrating that NLS recognition by importin is a key rate-determining step in nuclear import.
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PMID:Negative charge at the protein kinase CK2 site enhances recognition of the SV40 large T-antigen NLS by importin: effect of conformation. 987 90

Germline mutations of LKB1/Peutz-Jeghers syndrome gene predispose carriers to hamartomatous polyposis of the gastrointestinal tract as well as to cancer of different organ systems. Although Peutz-Jeghers syndrome patients frequently present with neoplasms of the colon, stomach, small intestine, pancreas, breast, ovaries, and cervix, somatic mutations appear to be rare in the sporadic tumor types thus far studied (colorectal, gastric, testicular, and breast cancers). To evaluate whether somatic mutations of LKB1 contribute to the tumorigenesis of yet unstudied tumor types, we screened 14 cell lines and 129 tumor specimens from different cancers for a genetic defect in LKB1. Six melanoma and eight myeloma cell lines were scrutinized for LKB1 somatic mutations by genomic sequencing. No changes were found in the coding LKB1 sequence and exon/intron boundaries. Next, we analyzed 12 pancreatic, 8 gastric, 12 ovarian granulosa cell, 26 cervical, 28 lung, 24 soft tissue, and 19 renal tumors by single-strand conformational polymorphism analysis. Three changes in LKB1 coding nucleotide sequence were identified. One base pair deletion at A957 and G958 substitution by T occurred in a cervical adenocarcinoma sample, resulting in a frameshift and premature stop codon at position 335. Substitution of A581 by T occurred in a lung adenocarcinoma sample, resulting in the change of aspartic acid at position 194 to valine. A loss of another allele was detected in this sample. One silent change, C1257T, was found in a pancreatic carcinoma sample. The changes were not present in the matched normal tissue DNA samples. Our results suggest that mutational inactivation of LKB1 is a rare event in most sporadic tumor types.
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PMID:LKB1 somatic mutations in sporadic tumors. 1007 45


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