Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of Mabs, particularly those reactive with primary brain tumors but not with normal brain, provides a potential means of delivering therapeutic agents selectively to human malignant gliomas. Mab 81C6, an IgG2b immunoglobulin, which defines an epitope of the glioma-associated extracellular matrix protein tenascin, has been shown to bind to human glioma cell lines, glioma xenografts in nude mice, and primary human gliomas, but not to normal adult or fetal brain. To test the therapeutic potential of this Mab for targeted delivery of isotopes, nude mice bearing progressively growing s.c. xenografts of D-54 MG, a human glioma cell line, were given injections via the tail vein of either buffer, unlabeled 81C6, 131I-labeled 81C6, or 131I-labeled 45.6, a nonspecific control Mab of the same isotype. Specific activities of the Mab range from 6.0 to 15.5 mCi/mg with protein doses from 7.6 to 167 micrograms. The doses given by injection per animal for labeled 81C6 were 50, 250, 500, and 1000 mu Ci and 500 and 1000 mu Ci for 45.6. Tumor response was measured by growth delay in reaching 1000 or 5000 mm3 tumor volumes using the Wilcoxon rank sum test, and by comparing the proportion of tumors that had regression in volume after treatment using the Fisher exact test. Statistically significant growth delays at 1000 mm3 were noted in 1 of 3 experiments with 500 mu Ci 81C6 (P less than 0.001) and 2 of 3 for 1000 mu Ci 81C6 (P = 0.001 and less than 0.001). At 5000 mm3, statistically significant growth delays were seen with radiolabeled 81C6 in 2 of 2 experiments at 250 mu Ci (P = 0.01 and 0.02), 4 of 4 at 500 mu Ci (P = 0.03-less than 0.001), and 2 of 2 at 1000 mu Ci (P = less than or equal to 0.001) and with radiolabeled 45.6 in 1 of 1 at 1000 mu Ci (P = 0.01). The percentage of animals with tumor regression progressively increased with increasing doses of isotope. For radiolabeled 45.6, there were 0 of 10 regressors at 500 and 1 of 10 at 1000 mu Ci. For radiolabeled 81C6, there were 0 of 6 regressors at 50 mu Ci, 1 of 16 (6%) at 250 mu Ci, 7 of 38 (18%) at 500, and 15 of 28 (54%) at 1000 mu Ci. Statistically significant tumor regression was seen only at doses of 500 and 1000 mu Ci of 131I-81C6.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Therapeutic efficacy of antiglioma mesenchymal extracellular matrix 131I-radiolabeled murine monoclonal antibody in a human glioma xenograft model. 244 47

We have studied interactions of tenascin with two chondroitin sulfate proteoglycans, neurocan and phosphacan. Neurocan is a multi-domain proteoglycan with a 136-kDa core protein that is synthesized by neurons and binds to hyaluronic acid, whereas the 173-kDa core protein of phosphacan, which is synthesized by glia, represents an extracellular variant of the receptor-type protein tyrosine phosphatase RPTP zeta/beta. Keratan sulfate-containing glycoforms of phosphacan (designated phosphacan-KS) are also present in brain. Immunocytochemical studies of early postnatal rat cerebellum demonstrated that the localization of neurocan, phosphacan, and phosphacan-KS all overlap extensively with that of tenascin, an extracellular matrix protein that modulates cell adhesion and migration. Binding studies using purified proteins covalently attached to fluorescent microbeads demonstrated that proteoglycan-coated beads co-aggregated with differently fluorescing beads coated with tenascin. The co-aggregation was specifically inhibited by Fab' fragments of antibodies against tenascin or the proteoglycans and by soluble neurocan, phosphacan, and tenascin. A solid phase radioligand binding assay confirmed that neurocan, phosphacan, and phosphacan-KS bind to tenascin but not to laminin and fibronectin. Chondroitinase treatment of the proteoglycans or addition of free chondroitin sulfate had no significant effect, indicating that the binding activity is mediated largely via the core glycoproteins. Scatchard analysis demonstrated high affinity binding of 125I-phosphacan, phosphacan-KS, and neurocan to a single site in tenascin, and neurocan and various glycoforms of phosphacan all inhibited binding of 125I-phosphacan to tenascin. In studies of cell adhesion to proteins adsorbed to Petri dishes, phosphacan inhibited adhesion of C6 glioma cells to tenascin whereas neurocan had no effect. Our results suggest that tenascin binds phosphacan and neurocan in vivo and that interactions between chondroitin sulfate proteoglycans and tenascin may play important roles in nervous tissue histogenesis, possibly by modulating signal transduction across the plasma membrane.
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PMID:Interactions with tenascin and differential effects on cell adhesion of neurocan and phosphacan, two major chondroitin sulfate proteoglycans of nervous tissue. 751 60

Tenascin, an extracellular matrix protein that modulates cell adhesion, exists as a unique six-armed structure called a hexabrachion. The human hexabrachion is composed of six identical 320 kDa subunits and the structure is stabilized by inter-subunit disulfide bonds between amino-terminal segments. We have examined the biosynthesis of tenascin and its assembly into hexabrachions using pulsechase labeling of U-138 MG human glioma cells. Newly synthesized tenascin hexamers are secreted within 60 minutes of translation initiation. Intracellularly, as early as full length tenascin can be detected in pulse-labeled cell lysates, it is already in hexameric form. No precursors, such as monomers, dimers, or trimers, were identified that could be chased into hexamers. This lack of assembly intermediates suggests that nascent tenascin polypeptides associate prior to completion of translation. In contrast, fibronectin monomers in the same lysates are gradually formed into disulfide-bonded dimers. Although hexamer assembly is rapid, the rate-limiting step in secretion appears to be transport to the medial Golgi as endoglycosidase H-resistance was not detected until after a 30 minute chase. These results provide evidence for a novel co-translational mechanism of tenascin assembly which would be facilitated by its length and by the amino-terminal location of the assembly domain.
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PMID:Rapid intracellular assembly of tenascin hexabrachions suggests a novel cotranslational process. 754 60

Tenascin, an extracellular matrix protein, is expressed in human gliomas in vitro and in vivo. The distribution of tenascin at the invasive edge of these tumors, even surrounding solitary invading cells, suggests a role for this protein as a regulator of glioma cell migration. We tested whether purified tenascin, passively deposited on surfaces, influenced the adhesion or migration of a human gliomaderived cell line, SF-767. Adhesion of glioma cells to tenascin increased in a dose-dependent fashion up to a coating concentration of 10 micrograms/ml. Higher coating concentrations resulted in progressively fewer cells attaching. Cell adhesion could be blocked to basal levels using anti-beta 1 integrin antibodies. In contrast, when anti-alpha v antibodies were added to the medium of cells on tenascin, cell adhesion was enhanced slightly. Using a microliter scale migration assay, we found that cell motility on tenascin was dose dependently stimulated at coating concentrations of 1 and 3 micrograms/ml, but migration was inhibited below levels of non-specific motility when tested at coating concentrations of 30 and 100 micrograms/ml. Migration on permissive concentrations of tenascin could be reversibly inhibited with anti-beta 1, while treatment with anti-alpha v antibodies increased migration rates. We conclude that SF-767 glioma cells express two separate integrin receptors that mediate contrasting adhesive and migratory responses to tenascin.
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PMID:Contrasting migratory response of astrocytoma cells to tenascin mediated by different integrins. 885 12

Malignant gliomas (primary brain tumors) aggressively invade the surrounding normal brain. This invasive ability is not demonstrated by brain metastases of nonglial cancers. The brain-specific, brain-enriched hyaluronan binding (BEHAB)/brevican gene, which encodes an extracellular hyaluronan-binding protein, is consistently expressed by human glioma and is not expressed by tumors of nonglial origin (Jaworski et al., 1996). BEHAB/brevican can be cleaved into an N-terminal fragment that contains a hyaluronan-binding domain (HABD) and a C-terminal fragment (Yamada et al., 1995). Here, using antisera to peptides in the predicted N-terminal and C-terminal proteolytic fragments, we demonstrate that the BEHAB/brevican protein is cleaved in invasive human and rodent gliomas. A role for this protein in glioma cell invasion was tested by transfecting a noninvasive cell line with the BEHAB/brevican gene. The noninvasive 9L glioma cell was transfected with either full-length BEHAB/brevican or the HABD and tested for invasion in in vitro and in vivo invasion assays. Although both constructs increased invasion in vitro, only the HABD increased invasion by tumors growing in vivo. Experimental intracranial tumors from full-length transfectants showed no increase in invasion over control tumors, whereas tumors from HABD transfectants showed a marked potentiation of tumor invasion, producing new tumor foci at sites distant from the main tumor mass. This work demonstrates a role for a brain-specific extracellular matrix protein in glioma invasion, opening new therapeutic avenues for a uniformly fatal disease.
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PMID:Expression of a cleaved brain-specific extracellular matrix protein mediates glioma cell invasion In vivo. 950 98

Tenascin (TN) is an extracellular matrix protein found in areas of cell migration during development and expressed at high levels in migratory tumor cells. TN was previously shown to support the attachment and migration of glioma cells in culture. To determine the domains responsible for glioma migration and attachment, we produced recombinant fusion proteins that collectively span the majority of the molecule including its epidermal growth factor-like repeats, fibronectin type III repeats and fibrinogen domain. These domains were tested for their ability to support migration of C6 glioma cells in an aggregate migration assay. A recombinant fusion protein including fibronectin type III (FNIII) repeats 2-6 (TNfn2-6) was the only fragment found to promote migration of C6 glioma cells at levels similar to that promoted by intact TN. Evaluation of smaller segments and individual FNIII repeats revealed that TNfn3 promoted migration and attachment of glioma cells and TNfn6 promoted migration but not attachment. While TNfn3 and TNfn6 promoted migration individually, the presence of both TNfn3 and TNfn6 was required for migration on segments of the FNIII region that included TNfn5. TNfn5 inhibited migration in a dose dependent manner when mixed with TNfn3 and also promoted strong attachment and spreading of C6 glioma cells. TNfn3 and TNfn6 promote cell migration and may function cooperatively to overcome the inhibitory activity of TNfn5. Additional cell attachment studies suggested that both beta1 integrins and heparin may differentially influence the attachment of glioma cells to TN fragments. Together, these findings show that C6 glioma cells integrate their response upon binding to at least three domains within TN.
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PMID:Domains of tenascin involved in glioma migration. 951 5

This study was undertaken to determine the effect of local hyperthermia on the tissue distribution of a chimeric human/mouse IgG2 monoclonal antibody, 81C6, reactive with the extracellular matrix protein tenascin, which is expressed at high levels in gliomas, carcinomas of the breast and prostate, and other neoplasms. The D-54 MG s.c. glioma xenograft was treated with hyperthermia by immersion of the tumor-bearing leg in a circulating water bath. By 4 h after injection (immediately after heating), administration of chimeric 125I-labeled 81C6 (ch81C6) concomitantly with a 4-h local hyperthermia treatment at 41.8 degreesC resulted in an increase in tumor uptake of monoclonal antibody from a median of 12% of injected dose/g of tumor in normothermic mice to 42% of injected dose/g in mice receiving local hyperthermia. The increased level of uptake persisted in the heated tumors over the first 48 h and at 96 h. Additionally, heating increased the tumor:blood ratio of ch81C6 more than 7-fold at 4 h postinjection. The rate of uptake was also dramatically improved, with 60 and 90% of the maximum level of uptake achieved by 4 and 24 h, respectively, in the hyperthermia-treated mice, whereas the normothermic mice reached only 31 and 69% of their maximum uptake at those time points. In summary, local hyperthermia enhanced the absolute level and the rate of tumor uptake as well as tumor:normal tissue ratios for ch81C6. This approach may facilitate the clinical application of radionuclides with shorter half-lives, such as 211At, for the therapy of solid malignancies.
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PMID:Local hyperthermia improves uptake of a chimeric monoclonal antibody in a subcutaneous xenograft model. 981 39

Tenascin-C (Tn-C) is an extracellular matrix protein with growth-, invasive-, and angiogenesis-promoting activities. Tn-C is upregulated during wound healing, tumorigenesis, and other pathological conditions. Highly malignant gliomas with poor prognosis exhibit high levels of Tn-C expression. Here we demonstrate that Tn-C RNA expression in glioma C6 cells is inhibited in a dose-dependent manner by retinoic acid (RA) and 1,25-dihydroxyvitamin D3 (1,25-D3). No additive or synergistic effects were found. Inhibition is maximum 24 hr after RA or 1,25-D3 treatment, prior to a delayed cytotoxic effect starting at day 4-5 of treatment, and correlates with a reduction in the synthesis of Tn-C protein. Tn-C expression is also inhibited, but to a lesser extent by prostaglandin D2 (PGD2). Furthermore, both RA and 1,25-D3, but not PGD2 abolish the induction of Tn-C by the tumor promoter 12-O-tetradecanoyl phorbol 13-acetate. The inhibition of Tn-C expression might be relevant for the anti-cancer activity of RA and 1,25-D3.
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PMID:Retinoic acid and 1,25-dihydroxyvitamin D3 inhibit tenascin-C expression in rat glioma C6 cells. 1050 85

Radioimmunopretargeting is based on the separate injection of a modified mAb and the radionuclide and most frequently exploits the very high avidity of biotin for streptavidin (SA). Currently, we are evaluating the therapeutic potential of directly labeled monoclonal antibody (mAb) 81C6, reactive with the extracellular matrix protein tenascin, in surgically created glioma resection cavity patients. To be able to investigate pretargeting in this setting, the synthesis of 81C6 mAb-SA conjugates was required. In the current study, we have evaluated five methods for preparing both murine 81C6 (m81C6) and human/mouse chimeric 81C6 (c81C6) SA conjugates with regard to yield, biotin-binding capacity, immunoreactivity, and molecular weight. The 81C6 mAb and SA were coupled by covalent interaction between sulfhydryl groups generated on the mAb via N-succinimidyl-S-acetylthioacetate, dithiothreitol or 2-iminothiolane (2IT), and maleimido-derivatized SA, prepared via sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) or N-succinimidyl-3-(2-pyridyldithio)-propionate. A noncovalent approach involving reaction of a biotinylated mAb, prepared using biotin caproate, and SA also was studied. The evaluation criteria were yield of mAb-SA 215 kDa monomer, as well as conjugate biotin-binding capacity and immunoreactive fraction. The optimal procedure involved activation of m81C6 or c81C6 with 30 equiv of 2IT and reaction of SA with 10 equiv of SMCC and yielded a conjugate with excellent biotin-binding capacity and immunoreactivity. The ((125)I-labeled m81C6)-2IT-SMCC-SA was stable and did not lose biotin-binding capacity after a 72 h incubation in human glioma cyst fluid in vitro. Although the conjugate was stable in murine serum in vivo, its biotin-binding capacity declined rapidly, consistent with high endogenous biotin levels in the mouse. After injection of the radioiodinated conjugate into athymic mice with subcutaneous D-54 MG human glioma xenografts, high tumor uptake (36.0 +/- 10.7% ID/g at 3 days) and excellent tumor:normal tissue ratios were observed.
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PMID:Preparation and characterization of anti-tenascin monoclonal antibody-streptavidin conjugates for pretargeting applications. 1050 55

We sought to characterize the pathway by which the multifunctional cytokine transforming growth factor-beta (TGF-beta) inhibits the proliferation of normal astrocytes, and we analyzed the alterations in the TGF-beta pathway in human glioma cell lines. Upon TGF-beta treatment, primary rat astrocytes showed a significant decrease in DNA synthesis upon thymidine incorporation with a cell cycle arrest in the G(1) phase. Western analysis of the astrocytes revealed that the expression of the cyclin-dependent kinase inhibitor (CdkI) p15(INK4B) was significantly up-regulated upon TGF-beta treatment without a change in other CdkI levels. The retinoblastoma protein (Rb) became hypophosphorylated, and Cdk2 activity decreased. Analysis of Smad3 null mouse astrocytes showed a significant loss of both TGF-beta-mediated growth inhibition and p15(INK4B) induction compared with wild-type mouse astrocytes. Infection of rat astrocytes by SMAD3 and SMAD4 adenoviruses failed to induce increased expression of p15(INK4B), implying indirect transcriptional regulation of p15(INK4B) by SMAD3. High-grade human gliomas secrete TGF-beta, yet are resistant to its growth inhibitory effects. Analysis of the effects of TGF-beta on 12 human glioma cell lines showed that TGF-beta mildly inhibited the growth of six lines, had no effect on four lines, and stimulated the growth of two lines. The majority of glioma lines had homozygous deletions of the p15(INK4B) gene, except for two lines that expressed p15(INK4B) protein, which was induced further upon TGF-beta treatment. Three lines mildly induced CdkI p21(WAF1) expression in response to TGF-beta. Most tumor lines retained other TGF-beta-mediated responses, including extracellular matrix protein and angiogenic factor secretion, which may contribute to increased malignant behavior. This suggests that the loss of p15(INK4B) may explain, in part, the selective loss of growth inhibition by TGF-beta in gliomas to form a more aggressive tumor phenotype.
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PMID:Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. 1057 84


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