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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The detection of DNA variation in cancers is an important step in elucidating the mechanism of tumorigenesis. Using the strategy of multipoint genome analysis we detected many differences between glioma-derived and constitutional DNA by customary DNA fingerprinting with simple repetitive oligonucleotide probes. Amplification of the epidermal growth factor receptor (EGFR) gene has been found to be easily detectable as new or highly intensified bands in one-dimensional (1-D) DNA fingerprints of glioblastoma DNA generated with probes (GTG)5 or (GT)8. However, in most low-grade astrocytomas, 1-D DNA fingerprinting has failed to reveal any genomic abnormalities. In these cases a two-dimensional (2-D) technique was successfully employed that is based on size separation in neutral gels followed by sequence-dependent separation in denaturing gradient gels and hybridization with several mini- and microsatellite core probes. The hundreds of spots visualized with this technique were used to detect subtle changes probably occurring as the initial steps of tumorigenesis in human gliomas. On average, five of the approximately 580 spots generated by probes CAC and 33.6 were found to be altered in tumor DNA; 80% of the alterations were spot losses, the rest being spot gains or amplifications. Computer-based image analysis using an external lambda marker provided a stringent way to compare spot patterns generated by 2-D DNA fingerprinting. In comparisons performed between typing patterns generated on the same gel, 99% of truly identical spots were confirmed by the software. In intergel comparisons 84% of identical spots were matched on the basis of the marker information alone.
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PMID:Parallel genome analysis by one- and two-dimensional DNA fingerprinting in human gliomas. 858 61

Gliomas affect 15,000 to 17,000 Americans every year and carry a dismal prognosis. The potential of immunologically mediated diagnosis and therapy, although greatly enhanced since the advent of monoclonal antibodies, has not been fully realized due to significant problems, most especially the challenge of identifying antigenic molecules specific to glial tumors. Other problematic issues include antigen-associated factors such as heterogeneity, modulation, shedding, and cross-reactivity with normal cells, and factors associated with therapeutic agent delivery, typically variable tumor perfusion and unfavorable diffusional forces in tumor microenvironment. An understanding of these problems called for the delineation of operationally specific antigens (tumor-associated antigens not expressed by the normal central nervous system) combined with the use of compartmental therapeutic approaches to increase the specificity of therapy. Numerous antigens have been identified and are classified as extracellular/matrix-associated, membrane-associated, and intracellular antigens. Nevertheless, only a few have been demonstrated to be of significant therapeutic and diagnostic utility. These few include the extracellular matrix-associated antigens tenascin and GP 240, defined by the monoclonal antibodies 81C6 and Mel-14, both of which are now in Phase I clinical trials, and membrane-associated ganglioside molecules, primarily 3', 6'-isoLD1, defined by the antibody DMAb-22. Recent identification of the overexpression of a deletion variant of the epidermal growth factor receptor (EGFRvIII) in up to 50% of the more malignant glial tumors and the subsequent creation of monoclonal antibodies that are specific to this molecule and do not recognize the wild-type EGFR provide the most exciting development yet in the design of specific antiglioma immunoconjugates. In addition, the tumor-specific nature of EGFRvIII combined with improved knowledge of immune mechanisms, especially in the context of the central nervous system, will facilitate the design of highly selective cell-mediated therapeutic approaches with a view toward obtaining tumor-specific immunity.
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PMID:Tumor antigens in astrocytic gliomas. 858 61

Astrocytic neoplasms show a high incidence of elevated or mutated epidermal growth factor receptor (EGFR) expression. Although proliferative effects from EGFR activation are well described, the role that changes in this receptor play in glioma growth and migration remain poorly addressed. This report characterizes changes in the levels of EGFR expression in three glial tumors at initial presentation (resection) and at the time of recurrence. By quantitative flow cytometry the mean level of EGFR expression increased, decreased, or remained the same in different recurrent astrocytomas relative to their primary tumor cells. Immunocytochemistry for EGFR on monolayer cells corroborated the level of expression in the recurrent tumors relative to their matched primary specimen. Immunoprecipitation indicated that 170 kd EGFR was expressed in each of the tumors, and showed normal down regulation following treatment with EGF. Proliferation response to EGF was seen in only 1/6 instances, but was concentration-dependent when observed. Stimulated migration of the cells was frequently seen and was also concentration-dependent on EGF; the magnitude of response was related to the relative level of 170 kd EGFR expression in the cells. EGFR immunostaining of tissue sections from the tumors confirmed the levels of EGFR expressed in primary and recurrent astrocytomas as was seen in the cultured cells. These results indicate that the relative levels of EGFR in early passage cell cultures from glioma specimens concurs with the measured tissue levels of expression. Human glioma cells are more responsive to migration induction than proliferation induction by EGF.
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PMID:Proliferation and motility responses of primary and recurrent gliomas related to changes in epidermal growth factor receptor expression. 869 21

The effects of a new epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, tyrphostin AG 1478, were tested on three related human glioma cell lines: U87MG, which expressed endogenous wild-type (wt) EGFR, and two retrovirally infected U87MG cell populations which over-expressed either wt (U87MG.wtEGFR) or truncated EGFR (U87MG. delta EGFR). Although AG 1478 inhibited cell growth, DNA synthesis, EGFR tyrosine kinase activity, and receptor autophosphorylation of each cell line in a dose-dependent manner, it was significantly more potent in U87MG. delta EGFR cells than in the other two cell lines. The increased inhibitory response of U87MG. delta EGFR cells was due to a greater sensitivity of the constitutively autophosphorylated Mr 140,000 and 155,000 delta EGFR species to AG 1478. These results suggest that AG 1478 is a relatively specific inhibitor of the delta EGFR, and this finding may have important therapeutic implications since the delta EGFR occurs frequently in glioblastomas and in breast, lung, and ovarian cancers.
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PMID:Tyrphostin AG 1478 preferentially inhibits human glioma cells expressing truncated rather than wild-type epidermal growth factor receptors. 875 45

Monocytes/macrophages frequently infiltrate malignant gliomas and play a central role in the tumor-associated immune response as they process tumor antigen and present it to T-lymphocytes. Findings have accumulated that peripheral blood monocytes leaving the cerebral circulation become microglial cells and vice versa and that monocytes/macrophages may stimulate malignant tumor growth by some unknown mechanism. Most malignant gliomas express growth factor receptors, for example epidermal growth factor receptor (EGFR). The aim of this study was to determine whether peripheral blood monocytes of glioma patients release EGF, the appropriate ligand of gliomacell membrane-bound EGFR. Long-term cultured peripheral blood monocytes from 14 patients with malignant gliomas were compared to those from 12 controls (seven with nontumorous disease and five healthy individuals). Using an enzyme-linked immunosorbent assay for EGF, the EGF content of cell culture supernatants was determined at Days 7, 21, and 100 of culture. The EGF content (mean +/- standard error) of supernatants was 5.9 +/- 0.2 pg/ml/10(3) glioma monocytes versus 1.3 +/- 0.1 pg/ml/10(3) control monocytes at Day 7 of culture, 22.9 +/- 0.8 pg/ml/10(3) glioma monocytes versus 1.8 +/- 0.9 pg/ml/10(3) control monocytes at Day 21 of culture, and 23.4 +/- 0.7 pg/ml/10(3) glioma monocytes, and below detection levels for control monocytes at Day 100 of culture. Steroid treatment of glioma patients did not influence the EGF release of cultured monocytes. These data indicate that glioblastoma-associated peripheral blood monocytes may be distinct from those of healthy individuals. Moreover, this study indicates that subtypes of glioma-associated peripheral blood monocytes may support immunosuppression and promote growth of malignant glioma by releasing unusually high amounts of EGF.
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PMID:Glioblastoma-associated circulating monocytes and the release of epidermal growth factor. 881 68

Cancer has been proposed to develop by a process of stepwise accumulation of growth-advantageous genetic alterations which result in the evolution of clones which are outgrowths of such rare cells [1]. This model has recently been extensively tested in human gliomas, the most common primary tumor of the adult central nervous system. Temporal disease progression involves an interplay between growth-suppressing and growth-promoting genes. Specifically for gliomas, genetic studies have indicated loss of germline heterozygosity for chromosome 17p; mutation of the p53 gene; overexpression of the platelet-derived growth factor-alpha receptor; allelic losses of chromosomes 22q, 13q, and 19q; deletion of the interferon-alpha and beta and CDKN2 loci on chromosome 9p; amplification and rearrangement of the epidermal growth factor receptor gene, and monosomy of chromosome 10. The following discussion details these genetic alterations and their consequences for the biology of glioma progression with the ultimate aim of providing new avenues for clinical intervention.
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PMID:Molecular biology of malignant degeneration of astrocytoma. 881 14

The genes involved in the genesis and progression of adult astrocytic tumors have been an area of considerable investigation. The tumor suppressor gene, p53, has been implicated, as has the epidermal growth factor receptor gene. Additional currently unidentified genes lie on chromosomes 10 and 19. Interestingly, work on pediatric astrocytomas suggests that the genes involved are different. p53 is rarely mutated in pediatric tumors, the epidermal growth factor receptor gene is rarely amplified or mutated, and chromosome 10 deletions are rare. The only pediatric tumor that seems to mimic the findings in adult tumors is brainstem glioma, perhaps explaining the uniformly grim prognosis in this type of tumor. In the pilocytic astrocytoma of childhood, mutations in the neurofibromatosis type I gene have been implicated in tumor development. In this review, the oncogenesis of pediatric gliomas is discussed and compared and contrasted to what is known about tumors.
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PMID:Molecular biology of pediatric gliomas. 883 57

Pleomorphic xanthoastrocytoma (PXA) is a low-grade glioma that may recur as a malignant diffuse astrocytoma such as glioblastoma (GBM). While the molecular genetic basis of diffuse astrocytomas has been studied extensively, PXAs have not been analyzed in detail. We, therefore analyzed DNA from archival primary and recurrent PXAs from eight patients (three grade II PXAs without recurrence, one grade II PXA with recurrence as grade II PXA, two grade II PXAs with progression to GBM, and two grade III anaplastic PXAs with recurrence as grade III anaplastic PXA or GBM) for genetic changes associated with diffuse astrocytomas. Single-strand conformation polymorphism analysis of p53 exons 5-8 revealed migration shifts in two cases, one primary PXA without recurrence and one recurrent grade II PXA in which the primary tumor did not show a shift. DNA sequencing showed two missense mutations in codons 220 (exon 6) and 292 (exon 8), respectively, mutations which have not been previously noted in astrocytomas. Differential polymerase chain reaction analysis demonstrated epidermal growth factor receptor gene amplification in only one tumor, a GBM without allelic loss of chromosome 10 that was the second GBM recurrence of an initial grade II PXA. Loss of heterozygosity studies on tumors from five patients, using three microsatellite polymorphisms on chromosome 10q and three on chromosome 19q, did not disclose allelic loss in any recurrent tumor. These findings suggest that the genetic events that underlie PXA formation and progression may differ significantly from those involved in diffuse astrocytoma tumorigenesis.
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PMID:Molecular genetic alterations in pleomorphic xanthoastrocytoma. 883 42

Human high-grade glioma cell lines (A1207, U-87MG, U-373MG, and F39) with high levels of epidermal growth factor receptor (EGF-R) expression were incubated for 2-48 h with 1 microCi/ml of the EGF-R-specific 125I-MAb 425 and measured for surface-bound, cytoplasmic, and nuclear radioactivity. The A1207 and U-373MG cell lines showed the highest surface-bound radioactivity with 215.9 +/- 8.7 nCi (30 h) and 287.8 +/- 23.2 nCi (24 h)/10(6) cells, respectively, whereas the U-87MG and the F39 cell lines bound significantly less antibody (48.8 +/- 5.4 nCi [48 h] and 31.1 +/- 0.7 nCi [24 h]). Surface-bound antibody was efficiently internalized into the cytoplasm. The U-373MG, U-87MG, and A1207 cell lines achieved 19.8% +/- 2.1 internalization of the surface-bound antibody in contrast to > 40% for the F39 cell line. Only the A1207 cell line showed significant nuclear radioactivity. There was no correlation between the reported EGF-R number and amount of antibody bound or internalized. We conclude that binding and uptake of the 125I-MAb 425 is specific for human glioma cells and shows saturation kinetics independent of receptor density.
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PMID:In vitro evaluation of iodine-125-labeled monoclonal antibody (MAb 425) in human high-grade glioma cells. 893 81

A small series of 2,2'-diselenobis(1H-indoles) was synthesized as redox-modified congeners of our earlier reported 2,2'-dithiobis(1H-indole) series. Utilizing chemistry similar to that developed earlier for the disulfur series, compounds were made from 2-halogeno-3-indolecarboxylic acid precursors bearing various polar functionality at the C-3 position and small alkyl substituents at the N-1 position of the indole nucleus. Additional compounds were derived from (R)- or (S)-tryptophan via a novel application of diselenium dichloride as an electrophilic source of diselenium, and a much improved process to a 2,2'-dithiobis(1H-indole) congener was developed utilizing disulfur dichloride as a source of disulfur. Against isolated epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), and v-src tyrosine kinases, compounds in this series displayed broad inhibitory activity with IC50 = 0.9 to > 100 microM vs EGFr, 3.4 to > 50 microM vs PDGFr, and 0.4-6.7 microM vs v-src. In general, compounds derived from tryptophan displayed the greatest potency against EGFr and those from 2-halogeno-3-indolecarboxylic acids greater potency against PDGFr and v-src. Enzyme kinetics studies showed that both classes of compounds display primarily noncompetitive inhibition with respect to either ATP or peptide substrate. The sulfhydryl reducing agent dithiothreitol (DTT) caused a general decrease in inhibition of the EGFr and v-src tyrosine kinases by both the diselenium and disulfur series with the reversal of enzyme inhibition occurring less readily within the diselenium series. In whole cell studies, compounds of this class were growth inhibitory against Swiss 3T3 mouse fibroblasts with IC50 values from 0.5 to 19.5 microM, and the observed SAR was different from that of the 2,2'-dithiobis(1H-indoles). A comparative study in the same cell line on the effects of the 2,2'-diselenobis(1H-indole) derived from (R)-tryptophan vs its disulfur congener on growth factor mediated tyrosine phosphorylation showed that this compound significantly inhibited EGFr and PDGFr (in response to its ligand) autophosphorylation with complete suppression at 25 and 5 microM, respectively. Tyrosine phosphorylation of an 85 kDa protein typically phosphorylated in response to bFGF was also exquisitely sensitive to this compound, and it displayed inhibitory effects on DNA, RNA, and protein synthesis at submicromolar concentrations. The disulfur congener exhibited a qualitatively similar pattern; however, its potency was 10-fold less. This same diselenium/disulfur pair was evaluated in vivo against the B16 melanoma, colon carcinoma 26, and M5076 sarcoma murine tumors, and the A431 epidermoid, and C6 glioma human tumor xenografts. At maximum tolerated doses (1.8 and 5.0 mg/kg/injection, respectively), neither the diselenium nor disulfur congener was effective against the C6 glioma when administered intraperitoneally on a d1-9 schedule. Studies were also carried out against the A431 epidermoid xenograft to evaluate the same pair of compounds via continuous subcutaneous infusion from Alzet miniosmotic pumps. The maximum dose that could be administered daily was limited by compound solubility. Neither compound produced an antitumor effect in a 7-day continuous infusion study. In the 27-day study, the disulfur compound was inactive whereas the diselenium compound produced a 10.8-day growth delay without appreciable treatment related weight loss. The in vitro and in vivo findings offer a mechanistic rationale as to why the 2,2'-diselenobis(1H-indoles) are more potent inhibitors than their disulfur congeners.
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PMID:Tyrosine kinase inhibitors. 6. Structure-activity relationships among N- and 3-substituted 2,2'-diselenobis(1H-indoles) for inhibition of protein tyrosine kinases and comparative in vitro and in vivo studies against selected sulfur congeners. 904 31


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