Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A human glioblastoma cell line was found to express in vitro mRNA transcripts specific for insulin-like growth factor-II (IGF-II) and growth-hormone releasing-hormone (GHRH). In the absence of gross morphological changes, retinoic acid reduced the growth rate without major change of IGF-II mRNA expression, while alpha-difluoromethylornithine produced a complete growth arrest and a sharp decrease of IGF-II mRNA expression. Both reagents increased the expression of GHRH mRNA. Also in this glioblastoma cell line, like other neuroectodermal tumours, IGF-II mRNA is expressed independently from GHRH and seems to be parallel to growth rate.
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PMID:IGF-II mRNA expression in LI human glioblastoma cell line parallels cell growth. 143 9

The prognosis of glioblastoma multiforme remains poor despite advances in treatment by surgery, irradiation, and chemotherapy. Many malignant gliomas overexpress growth factor receptors. The possibility of targeting these receptors with selective cytotoxic molecules constructed by fusing deoxyribonucleic acid (DNA)-encoding mutant forms of Pseudomonas exotoxin A (PE) with complementary DNA-encoding growth factors was investigated. Several recombinant toxins have been produced, including those in which transforming growth factor (TGF)-alpha, insulin-like growth factor (IGF)-I, and acidic fibroblast growth factor (FGF) were fused to mutant forms of PE lacking the native cell-binding domain. These recombinant proteins are cytotoxic to cells that express specific cell-surface receptors. The cytotoxic activity of TGF-alpha, IGF-I, and acidic FGF chimeric toxins was tested in vitro against human glioblastoma cell lines. Each recombinant toxin exhibited potent and specific killing of cells. The TGF-alpha-PE40 construct was cytotoxic to seven of the eight cell lines and was active at concentrations as low as 0.5 ng/ml (1.1 x 10(-11) M). The acidic FGF-PE40 toxin was also active on seven of the eight cell lines but was 50-fold less active than the TGF-alpha-PE40. The IGF-I-PE40 construct was active on only two cell lines. To determine the possible therapeutic effect in animals, TGF-alpha-PE40 was administered to nude mice bearing subcutaneous human glioblastoma xenografts. The animals were treated for 7 days via a continuous infusion pump placed in the peritoneal cavity. A constant serum level of TGF-alpha-PE40 was achieved that was nontoxic to the mice yet caused a reduction in tumor volume and retarded growth beyond the treatment period. The overexpression of the epidermal growth factor receptor in glioblastomas multiforme and the potency and specificity of the TGF-alpha-PE40 construct designed to target this receptor suggests that TGF-alpha-PE40 has the potential to be an effective antitumor agent for the adjuvant therapy of these carcinomas.
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PMID:Cytotoxicity and antitumor effects of growth factor-toxin fusion proteins on human glioblastoma multiforme cells. 769 18

Homopurine (AG) and homopyrimidine (CT) oligodeoxyribonucleotides predicted to form triple-helical (triplex) structures have been shown to specifically suppress gene expression when supplied to cultured cells. Here we present evidence that homopurine RNA (effector) sequences designed to form a triplex with a homopurine. homopyrimidine sequence 3' to the termination codon of the insulin-like growth factor type I receptor (IGF-IR) structural gene can efficiently suppress IGF-IR gene transcription. Transfection vectors were constructed to drive transcription of either AG or CT variant triplex-forming strands. To increase the probability of obtaining stable transfectants with adequate expression of effector sequences, these were designed to be transcribed together with cDNA sequences conferring neomycin resistance as a fusion transcript. Rat C6 glioblastoma cells transfected with the AG variant showed dramatic reduction of IGF-IR transcripts compared with untransfected cells. The AG transfectants also exhibited marked down-regulation of the IGF-I, and an enhanced accumulation of serine protease inhibitor nexin-I mRNA. Similar changes in gene expression were observed following transfection of C6 cells with constructs transcribing antisense RNA to IGF-IR transcripts, but were not observed in C6 cells transfected with either the CT triplex variant or with vector lacking triplex-forming sequences. Moreover, C6 cells transfected with AG triplex variant displayed a dramatic inhibition of tumor growth when injected into nude mice. The results suggest that a triple-helix strategy can be used to inhibit transcription elongation of the IGF-IR gene, and emphasize the efficacy of triplex-mediated gene inhibition in an animal model.
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PMID:Suppression of insulin-like growth factor type I receptor by a triple-helix strategy inhibits IGF-I transcription and tumorigenic potential of rat C6 glioblastoma cells. 915 64

The current studies quantified the effect of the multivalent cations zinc, cadmium, lanthanum, chromium, and gold (Zn2+, Cd2+, La3+, Cr3+, and Au3+) on [125I]-insulin-like growth factor ([125I]-IGF) binding to T98G human glioblastoma cells. The major binding site for the IGFs on T98G cells is IGF binding protein-5 (IGFBP-5), as determined by affinity labeling. Competitive binding studies, using either [125I]-IGF-I or [125I]-IGF-II, indicated that La3+ and Cr3+ did not affect [125I]-IGF-I or [125I]-IGF-II binding to cell-associated IGFBP-5. Zn2+, Au3+, and Cd2+ depressed binding of both [125I]-IGF-I and [125I]-IGF-II. [125I]-IGF-I and [125I]-IGF-II binding resulted in nonlinear concave-down Scatchard plots, indicating the presence of high- and low-affinity equilibrium constant of association (Ka) sites. Assuming a preexisting asymmetric model with independent high (KaHi) and low (KaLo) sites; Zn2+, Cd2+, and Au3+ eliminated KaHi and Zn2+, and Au3+ lowered KaLo, compared with control values. The same results were found, independent of whether [125I]-IGF-I or [125I]-IGF-II was used. Similarly, assuming a ligand-induced model of negative cooperativity, all three cations eliminated the initial affinity for the high affinity sites (Ka), whereas Zn2+ and Au2+ reduced the final affinity for the low affinity sites (Kf). Dose-response studies indicated that Zn2+, Au3+, and Cd2+ depressed binding with half-maximal activities of approximately 20 microM, 14-60 microM, and 50-65 microM, respectively. Zn2+, Au3+, and Cd2+ bind to similar sites on proteins (a zinc-binding motif), indicating similar mechanisms of action. A zinc-binding motif is present within the IGFBPs but not the IGFs. We demonstrate, for the first time, that multivalent cations have the potential to modulate IGF activity by decreasing the amount of IGF bound to cell-associated IGFBP-5.
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PMID:Multivalent cations depress ligand binding to cell-associated insulin-like growth factor binding protein-5 on human glioblastoma cells. 952 81

Increased protein kinase C(alpha) (PKC(alpha)) expression in glioblastoma cells is associated with proliferation and resistance to drug-induced apoptosis by an undefined anti-apoptotic pathway. To clarify the role of PKC in apoptosis, we have investigated the effect of the selective PKC inhibitor Ro 31-8220 (3-[1-[3-(amidinothio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H -pyrrole-2,5-dione methanesulfonate) in two glioblastoma cell lines whose proliferation is dependent on high levels of PKC(alpha). U-87 and A172 cells treated with an IC50 of Ro 31-8220 exhibited nucleosomal DNA fragmentation that coincided with an increase in the number of apoptotic cells. This effect was preceded by the rapid nuclear accumulation of wild-type p53 within 2 hr, and an increased level of the pro-apoptotic protein, insulin-like growth factor-1-binding protein-3, (IGFBP3) but not other p53-regulated proteins such as p21WAF1 or Bax. Accumulation of p53 was also associated with the hypophosphorylated and activated form of the retinoblastoma tumor suppressor protein (RB) at later times after treatment. These results suggest that PKC(alpha) suppresses apoptosis in glioblastoma cells primarily by restricting the accumulation of p53 and the expression of insulin-like growth factor-1-binding protein, as well as by maintaining RB in an inactive hyperphosphorylated state.
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PMID:Induction of apoptosis in glioblastoma cells by inhibition of protein kinase C and its association with the rapid accumulation of p53 and induction of the insulin-like growth factor-1-binding protein-3. 963 8

Various growth factors and basement membrane proteins have been implicated in the pathobiology of astrocytomas. The goal of this study was to determine the relative contribution of these two factors in modulating the phenotype of U-373 MG glioblastoma cells as determined by the expression of the intermediate filament proteins glial fibrillary acidic protein, vimentin, and nestin. For these determinations, cells plated in serum-free medium were treated either with growth factors binding to tyrosine kinase receptors including transforming growth factor-alpha, epidermal growth factor, platelet-derived growth factor-AA, basic fibroblast growth factor, and insulin-like growth factor-1 or with basement membrane proteins including collagen IV, laminin, and fibronectin. The changes in the expression levels of intermediate filament proteins in response to these treatments were analyzed by quantitation of immunoblots. The results demonstrate that collagen IV and growth factors binding to tyrosine kinase receptors decrease the glial fibrillary acidic protein content of U-373 MG cells. Growth factors binding to tyrosine kinase receptors also decrease the vimentin content of these cells but do not affect their nestin content. On the other hand, basement membrane proteins decrease the nestin content of U-373 MG cells but do not affect their vimentin content. The significance of these results with respect to the role played by different factors in modulating the phenotype of neoplastic astrocytes during tumor progression is discussed.
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PMID:Effects of growth factors and basement membrane proteins on the phenotype of U-373 MG glioblastoma cells as determined by the expression of intermediate filament proteins. 977 47

Antagonists of growth hormone-releasing hormone(GH-RH)inhibit the growth of various cancers by mechanisms that involve the suppression of the insulin-like growth factor (IGF)-I and/or IGF-II. In view of the importance of the IGF system in glioma tumorigenesis, the effects of GH-RH antagonists MZ-5-156 and JV-1-36 were investigated in nude mice bearing subcutaneous and orthotopic xenografts of U-87MG human glioblastomas. After 4 weeks of therapy with MZ-5-156 or JV-1 -36 at the dose of 20 microg/day per animal, the final volume of subcutaneous U-87MG tumors was significantly (P < .01) decreased by 84% and 76%, respectively, as compared with controls. Treatment with GH-RH antagonists also reduced tumor weight and the levels of mRNA for IGF receptor type I (IGFR-I). A reduction in the mRNA levels for IGF-II was found in tumors of mice treated with MZ-5-156. Treatment with MZ-5-156 or JV-1 -36 also extended the survival of nude mice implanted orthotopically with U-87MG glioblastomas by 81% (P < .005) and 18%, respectively, as compared with the controls. Exposure in vitro to GH-RH antagonists MZ-5-156 or JV-1 -36 at 1 microM concentration for 24 hours decreased the tumorigenicity of U-87MG cells in nude mice by 10% to 30% and extended the latency period for the development of subcutaneous palpable tumors by 31% to 56%, as compared with the controls. Exposure of U-87MG cells to GH-RH antagonists in vitro also resulted in a time-dependent increase in the mRNA levels of IGFR-II or a decrease in the mRNA levels of IGFR-I. mRNA for GH-RH was detected in U-87MG cells and xenografts implying that GH-RH may play a role in the pathogenesis of this tumor. Our results suggest that GH-RH antagonists MZ-5-156 and JV-1-36 inhibit the growth of U-87MG human glioblastoma by mechanisms that involve the suppression of IGF system. Antagonistic analogs of GH-RH merit further development for the treatment of malignant glioblastoma.
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PMID:Antagonists of growth hormone-releasing hormone inhibit the growth of U-87MG human glioblastoma in nude mice. 1093 10

Human central nervous system tumors and glioma cell lines highly express the insulin-like growth factor-binding protein (IGFBP)-2. As IGFBP-2 can affect tumor growth, we studied the relationship between IGFBP-2 expression and the malignancy of brain tumors in vivo. To do so, we investigated by immunohistochemistry the accumulation of IGFBP-1, -2, and -3 in 50 human gliomas classified by the WHO Malignancy Scale. Double labeling using anti-CD68 (monocytes/macrophages), antiglial fibrillary acidic protein, and anti-CD3 (T cells) antibodies was performed to further characterize the IGFBP-1, -2, and -3(+) cells. The expression of IGFBP messenger RNAs (mRNAs) was tested by RT-PCR in tumor samples from nine gliomas of different grades and in eight cell lines representing the cellular composition of human glioma. As controls, the accumulation of IGFBP-2 was investigated in normal brain and in the rat C6 glioblastoma model. IGFBP-1 and -3 accumulated in endothelial and macrophage/microglial cells. IGFBP-2(+) macrophage/microglial and glioma cells clustered in the immediate vicinity of focal necrosis of the human gliomas as well as of the rat C6 glioblastoma. The labeling score of IGFBP-1 accumulation in endothelial cells correlated negatively (P: = 0.0229), and that of IGFBP-2 accumulation in glioma cells correlated positively (P: < 0.0006) with the tumor grade of the gliomas. In addition, RT-PCR analysis confirmed mRNA expression of IGFBP-1, -2, and -3 by the gliomas and glial cells. Small amounts of IGFBP-1 and -3 mRNA, but high amounts of IGFBP-2 mRNA, were detectable in macrophage-like and glioma cell lines. The results suggest cell type-specific accumulation of IGFBP-1, -2, and -3 in human glial tumors of the brain. The increase in IGFBP-2 expression with this malignancy suggests a role of IGFBP-2 in the biology of human gliomas.
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PMID:In vivo expression of insulin-like growth factor-binding protein-2 in human gliomas increases with the tumor grade. 1125 Sep 47

Various immunotoxins have been developed for the treatment of cancer. The toxin is internalized by target cells through cell-surface receptors, and it is essential for these receptors to be expressed for the immunotoxin to have specific anti-tumor activity. Radiation therapy is one of the main treatment modalities for primary malignant brain tumors. The purpose of this study was to determine whether radiation influences the expression of cell-surface receptors. Cells of one human medulloblastoma (Daoy) and two glioblastoma (U373-MG and T98-G) cell lines were tested by exposing the cells to a single dose of 5 Gy gamma rays. Expression of transferrin receptors, type-1 insulin-like growth factor receptors (IGF1R), and interleukin 4 receptors (IL4R) was measured by flow cytometry analysis on unirradiated cells and on cells 3 to 120 h after irradiation. In Daoy cells, the absolute expression index of transferrin receptors increased during the 24 h after irradiation with the greatest change of 26% above control at 9 h. The absolute expression index of IGF1R increased 26.5% above control at 12 h. The absolute expression index of IL4R decreased 9 h after irradiation. In U373-MG cells the absolute expression index of transferrin receptors increased during the 24 h after irradiation, and the greatest increase was 45% above control at 9 h. The absolute expression index of IGF1R increased during the 12 h after irradiation with a maximum increase of 33% above control at 6 h. The absolute expression index of IL4R decreased with time after irradiation. In T98-G cells, the absolute expression index of both transferrin receptors and IL4R decreased after irradiation. The results suggest that the expression of growth factor receptors on brain tumor cells may be influenced by radiation. The effect of ionizing radiation on receptor expression should be considered when administration of targeted toxin is combined with radiation. Similar studies with other growth factor receptors used in targeted toxin therapy are recommended.
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PMID:Changes in expression of transferrin, insulin-like growth factor 1, and interleukin 4 receptors after irradiation of cells of primary malignant brain tumor cell lines. 1285 34

The growth of most tissues is markedly depressed as a result of zinc deficiency by uncharacterized mechanisms that clearly involve the insulin-like growth factor (IGF) system. Herein, we describe the mechanism by which zinc (Zn2+) maintains IGF-II in an active form by directly regulating IGF-II binding to IGF-binding proteins (IGFBPs) and the type 1 IGF receptor (IGF-1R). The specificity of Zn2+ effects was confirmed by using other cations that can (Cd2+ and Au3+) or cannot (La3+) mimic Zn2+ actions. Human fibroblasts, glioblastoma cells, and murine myoblasts were used to determine the kinetics of IGF-II binding to cell surface IGFBP-3, IGFBP-5, and the IGF-1R, respectively. Zn2+, Cd2+, and Au3+, but not La3+, decreased total binding and the affinity for [125I]IGF-II association with IGFBP-3 and IGFBP-5. These effects were a result of lowered rate of ligand association without affecting rate of dissociation. In contrast, Zn2+ enhanced [125I]IGF-II binding to the IGF-1R by enhancing the rate of ligand association and decreasing the rate of dissociation. Our previous work had shown that Zn2+ acts at physiological levels to alter IGF binding. Together with the current work, these findings imply that Zn2+ acts in vivo to prevent secreted IGF-II from binding to IGFBP-3 and IGFBP- 5, thus maintaining IGF-II in an "active state," i.e., readily available for IGF-1R association.
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PMID:Zinc alters the kinetics of IGF-II binding to cell surface receptors and binding proteins. 1451 14


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