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)

The tumor suppressor gene p53 has been identified as the most frequent target of genetic alterations in human cancers. Cancer-related mutations in the human p53 protein tend to cluster in four of the five highly conserved domains of the protein, and, in particular, in the central region of domain IV from residues 241 to 253. Using conformational energy analysis based on ECEPP (Empirical Conformational Energies for Polypeptides Program), we have determined the preferred three dimensional structures for this tridecapeptide sequence for the human wild-type p53 protein and four cancer-related mutant p53 proteins (Ala 245, Ile 246, Trp 248, Ser 249). The results show that the mutant peptides adopt conformations that are distinctly different from that of the wild-type peptide. These results are consistent with experimental conformational studies demonstrating altered detectability of antigenic epitopes in murine wild-type and mutant p53 proteins. These results suggest that the oncogenic effects of human mutant p53 proteins may be mediated by distinct local conformational changes in the protein.
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PMID:Conformational effects of selected cancer-related amino acid substitutions in the p53 protein. 146 8

Boron neutron capture therapy (BNCT) involves administration of a boron compound followed by neutron irradiation of the target organ. The boron atom captures a neutron, which results in the release of densely ionizing helium and lithium ions that are highly damaging and usually lethal to cells within their combined track length of approximately 12 microns. Prior to Phase I clinical trials for patients with malignant gliomas, mice with glioma 261 intracerebral tumors were fed D,L-3-(p-boronophenyl)alanine and irradiated with total tumor doses of 1000-5000 RBE-cGy of single fraction thermal neutrons to determine the maximum tolerated dose and effect on survival. These mice were compared to mice that received D,L-3-(p-boronophenyl)alanine alone, neutron irradiation alone, photon irradiation alone, or no treatment. Additional normal mice received escalating doses of neutron irradiation to determine its toxicity to normal brain. BNCT caused a dose-dependent, statistically significant prolongation in survival at 1000-5000 RBE-cGy. At 3000 RBE-cGy, median survival rates of the BNCT and untreated control groups were 68 and 22 days, respectively, with a long-term survival rate of 33%. At 4000 RBE-cGy, median survival was 72 and 21 days, respectively, with a long-term survival rate of 43%. At lower radiation doses, the extended survival was comparable between the BNCT and photon-irradiated mice; however, at 3000 and 4000 RBE-cGy the median survival of BNCT-treated mice was significantly greater than photon-irradiated mice. The maximum tolerated single fraction dose to normal brain was approximately 2000 RBE-cGy.
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PMID:Boron neutron capture therapy for murine malignant gliomas. 151 33

The signal transduction mechanisms involved in the regulation of phagocytosis are largely unknown. We have recently shown that in neutrophils, when IgG-mediated phagocytosis is stimulated by formyl-methionyl-leucyl-phenyl-alanine (fMLP), the enhanced ingestion is dependent on the increase in [Ca2+]i which results from ligation of Fc receptors by the IgG-coated target (Rosales, C., and Brown, E. (1991) J. Immunol. 146, 3937-3944). Now, we have studied the mechanism by which this rise in [Ca2+]i occurs. Aggregated IgG, the monoclonal antibody 3G8 (which recognizes Fc receptor type III), and insoluble immune complexes caused an increase in [Ca2+]i. The rise in [Ca2+]i induced by Fc receptor ligation was resistant to pertussis toxin. In contrast, fMLP induced a rise in [Ca2+]i which was inhibited by pertussis toxin. fMLP-induced [Ca2+]i was accompanied by an accumulation of inositol 1,4,5-trisphosphate (IP3) which peaked by 15 s, and which was also abolished by pertussis toxin. IP3 accumulation after aggregated IgG, 3G8, or insoluble immune complexes was much less than after fMLP. Unlike [Ca2+]i rise induced by Fc receptor ligation, this small increase in IP3 was inhibited by pertussis toxin. These data demonstrated that the [Ca2+]i increase induced by Fc receptor ligation is not mediated by IP3. Immediate pretreatment of human polymorphonuclear neutrophils with optimal doses of fMLP also reduced subsequent increase in [Ca2+]i rise from thapsigargin, a sesquiterpene lactone tumor promoter that releases intracellular Ca2+ from IP3-sensitive stores without IP3 turnover. Similarly, to its effects on thapsigargin, fMLP inhibited the [Ca2+]i rise upon subsequent immune complex binding. Pretreatment of cells with immune complexes also prevented subsequent [Ca2+]i rise from thapsigargin and fMLP. These data demonstrate that IgG Fc receptor ligation and fMLP activation of human polymorphonuclear neutrophils use distinct signal transduction mechanisms to release Ca2+ from the same thapsigargin-sensitive intracellular pool. In contrast to fMLP, signal transduction for increased [Ca2+]i after Fc receptor stimulation does not involve a pertussis toxin-sensitive G protein, and is independent of IP3.
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PMID:Signal transduction by neutrophil immunoglobulin G Fc receptors. Dissociation of intracytoplasmic calcium concentration rise from inositol 1,4,5-trisphosphate. 153 82

Previous studies from this laboratory have described that LNCaP prostate tumor cells contain an androgen receptor (AR) with a point mutation in the steroid-binding domain (codon 868, Thr to Ala). This defect leads to a change in specificity of the AR. Estrogens, progestagens, and some anti-androgens (e.g., cyproterone acetate, hydroxyflutamide, nilutamide) stimulate LNCaP cell growth rate through the AR. The present studies indicate that not all anti-androgens showed agonistic effects with the mutated receptor. The growth rate of LNCaP cells did not increase with the anti-androgen ICI 176334, nor could this compound increase transcription activation of the reporter gene construct via the mutant receptor in a cotransfection system [HeLa cell cotransfection system with an androgen-regulated reporter gene construct (pG29G-tk-CAT) and the mutant receptor as trans-vector]. Interaction of the AR of LNCaP cells with heat-shock proteins was studied by isolation of the receptor with a specific monoclonal antibody and characterization of associated proteins. Hsp90, hsp70, and hsp56 were found to coprecipitate with the AR. Incubation of the cells at 37 degrees C with androgen (R1881, 10 nM) or the anti-androgen hydroxyflutamide, prior to receptor isolation, resulted in dissociation of the AR-heat-shock protein complex. This dissociation is paralleled by the transformation to a tight nuclear-binding form of the AR. In contrast, ICI 176334 could not induce a release of heat-shock proteins and did not increase nuclear binding, but inhibited the transformation process induced by R1881.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anti-androgens and the mutated androgen receptor of LNCaP cells: differential effects on binding affinity, heat-shock protein interaction, and transcription activation. 154 May 95

High-resolution 1H NMR spectroscopy has been used to measure the concentrations of metabolites (alanine, N-acetylaspartate, gamma-aminobutyric acid, glutamate, glutamine, aspartate, taurine, glycine, succinate, creatine, cholines, inositol, and glucose) in perchloric acid extracts of human epileptic cortex and brain tumors. All tissue was obtained by surgical biopsy, excised before thermal coagulation, and immediately frozen in liquid nitrogen. Lower levels of N-acetylaspartate and gamma-aminobutyric acid and a shift in the glutamate/glutamine ratio toward glutamine in the tumors reflect neuronal loss. Abnormal glucose metabolism (aerobic glycolysis) in the tumors gives decreased levels of succinate, glutamate, aspartate, glutamine, and creatine and generally increased concentrations of glycine and alanine. Differences in metabolite concentrations that may be of use in differential tumor diagnosis include lower creatine and inositol in meningiomas than in astrocytomas. Lower taurine differentiates benign from malignant astrocytomas. Malignant astrocytomas and metastatic tumors are more regionally heterogeneous than meningiomas or benign astrocytomas. Mannitol, administered perioperatively to all patients from whom tissue was obtained, was observed only in the spectra of extracts of tissue from tumors which enhanced on computerized tomographic imaging.
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PMID:High-resolution 1H NMR spectroscopy studies of extracts of human cerebral neoplasms. 155 19

The human prostate tumor cell line LNCaP contains an abnormal androgen receptor system with broad steroid binding specificity. Progestagens, estradiol and several antiandrogens compete with androgens for binding to the androgen receptor in the cells to a higher extent than in other androgen sensitive systems. Optimal growth of LNCaP cells is observed after addition of the synthetic androgen R1881 (0.1 nM). In addition, estrogens, progestagens and several antiandrogens do not inhibit androgen responsive growth, but have striking growth stimulatory effects and increase EGF receptor level and acid phosphatase secretion. We have found that the androgen receptor in the LNCaP cells contains a single point mutation changing the sense of codon 868 (Thr to Ala) in the ligand binding domain. Expression vectors containing the normal or mutated androgen receptor sequence were transfected into COS or HeLa cells. Androgens, progestagens, estrogens and several antiandrogens bind the mutated androgen receptor protein and activate the expression of an androgen-regulated reporter gene (GRE-tk-CAT), indicating that the mutation directly affects both binding specificity and the induction of gene expression. Interestingly, the antiandrogen casodex showed antiandrogenic properties in growth studies of LNCaP cells and did not induce reporter gene activity in Hela cells transfected with the mutant receptor. The mutated androgen receptor of LNCaP cells is therefore a useful tool in the elucidation of different levels of action of steroids and antisteroids.
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PMID:The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. 156 39

Mutation of the p53 gene, which plays an important role in the genesis of diverse human cancers, was investigated in 23 surgical specimens of human renal cell carcinoma using the polymerase chain reaction single-strand conformation polymorphism method of analysis. Only one of the 23 tumors (4.3%) carried a mutated p53 gene, which was present in exons 7-8. Direct DNA sequencing confirmed a point mutation at codon 276 (GCC to CCC) resulting in a substitution of alanine for proline. No specific clinicopathological characteristics were observed in the case with the p53 gene mutation in human renal cell carcinoma. These observations suggest that mutation of the p53 gene is rare and thus does not contribute significantly to the genesis of this tumor.
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PMID:Infrequent mutation of p53 gene in human renal cell carcinoma detected by polymerase chain reaction single-strand conformation polymorphism analysis. 158 82

Image-guided localized proton magnetic resonance (MR) spectroscopy of intracranial tumors was performed to correlate spectral patterns and histologic findings. Thirty-six patients were examined prior to any specific treatment. Evaluation based on signal intensity ratios showed that all tumor spectra differed from spectra of healthy brain tissue. Ratios of creatine to choline-containing compounds (Cr/Cho) and nitrogen acetyl-aspartate to Cho (NAA/Cho) were reduced significantly in all tumor spectra compared with spectra of normal tissue in contralateral brain hemispheres (P less than .005). Noncerebral tumors typically showed a vanishing or missing NAA signal, strongly reduced Cr signal, and additional signals, assigned to alanine in meningiomas and lipids in metastases. In contrast, 11 gliomas of grades 2 and 3 exhibited NAA/Cho ratios and Cr/Cho ratios that were less than normal but that were significantly larger (P less than .01) than corresponding values in eight meningiomas. Ten glioblastomas displayed spectra with various signal ratios, so no significant differences between them and other tumor types could be established. In nine gliomas a clearly detectable lactate signal was present. However, no direct correlation between lactate level and histologic tumor grading was found.
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PMID:Human brain tumors: spectral patterns detected with localized H-1 MR spectroscopy. 158 24

O6-Methylguanine-DNA methyltransferase plays an important role in preventing tumor induction. To elucidate the significance of a highly conserved amino acid sequence of methyltransferase protein, amino acid substitutions were introduced by site-directed mutagenesis of cloned cDNA for human methyltransferase and the activity and stability of mutant forms of enzyme were examined. When cysteine-145, to which the methyl transfer occurs, was replaced by other amino acids, all of the mutants isolated showed the methyltransferase-negative phenotype. From one of the negative mutants, methyltransferase-positive revertants were isolated, all of which carried codons for cysteine. Thus the cysteine residue is essential for acceptance of the methyl group and cannot be replaced by other amino acids. Using this negative and positive selection procedure, analyses were extended to other residues near the acceptor site. At the histidine-146 site, four substitutions (phenylalanine, methionine, asparagine and glutamine) exhibited the positive phenotype but the levels of methyltransferase activity in these mutants were low. With valine-148 substitutions there were six types of positive revertants, among which mutants carrying isoleucine, cysteine and alanine showed significantly high levels of methyltransferase activity. Some mutant forms of cDNA were expressed in methyltransferase-deficient human cells, and the results obtained with Escherichia coli cells were confirmed.
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PMID:Specific amino acid sequences required for O6-methylguanine-DNA methyltransferase activity: analyses of three residues at or near the methyl acceptor site. 158 96

The diagnostic values of CA 19-9 and CEA were evaluated in 187 cases (including 31 gastric, 41 colorectal, 12 pancreatic, 7 hepatobiliar and 5 hepatocellular carcinomas). These tumor markers were compared to the other laboratory parameters [hemoglobin, erythrocyte sedimentation rate, serum bilirubin, ASAT (aspartate amino transferase), ALAT (alanine amino transferase) GGT (gamma glutamil transpeptidase), ALP (alkaline phosphatase)]. The specificity of CA 19-9 was 89.5%, while the sensitivity of this tumor markers was 91.7% in pancreatic carcinoma, 54.8% in gastric carcinoma and 43.9% in colorectal carcinoma. The sensitivity of CEA only in colorectal patients was higher than that of CA 19-9 (specificity 73.9%, sensitivity 64.5%). Although the CA 19-9 and CEA are not known to give any cross-reaction with each other, simultaneous measurement and evaluation of these two tumor antigens did not result in a better diagnostic sensitivity. After undergoing a gastrointestinal carcinoma operation, CA 19-9 indicated the appearance of tumor recidiva with a 62% sensitivity. Calculated together with CEA the sensitivity elevated to 88.9%. In most of the patient with benign cholostasis, the CA 19-9 and CEA values were out of the normal range (53.3% and 36.4% respectively), so these tumor markers are not suitable to differentiate between benign and malign cholostasis. According to the authors, CA 19-9 is the most useful diagnostic tool to differentiate between pancreatic carcinoma and pancreatitis chronica (both group without cholostasis), as well as for monitoring the patients after surgery of a gastrointestinal cancer.
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PMID:[Diagnostic value of CA 19-9 and CEA in gastrointestinal pathology]. 160 81


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