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 cytotoxic activity of immunotoxins constructed with human diferric transferrin (Tfn) as the carrier ligand and an abrin variant Pseudomonas exotoxin A (PE) and the diphtheria toxin mutant cross-reacting material (CRM) 107 as the toxin moieties were studied in vitro. Three malignant human cell lines, the glioblastomas multiforme SNB19 and SF295 and the LOX melanoma, and a nonhuman control murine melanoma cell line B16 were assessed. The presence of transferrin receptors on the cell lines was confirmed by direct 125I-Tfn binding assays. The 50% protein synthesis inhibitory concentration (IC50) values for all cell lines demonstrated that Tfn-abrin variant and Tfn-PE had comparable potency and were both more effective than Tfn-CRM 107. Monensin, a carboxylic ionophore, potentiated the effect of Tfn-abrin variant against glioma cells approximately 35-fold with IC50 values of 4.0 x 10(-13) M and 4.7 x 10(-12) M for SNB19 and SF295, respectively. Cytotoxic activity of Tfn-abrin variant (with or without monensin) and Tfn-PE was correlated with the degree of Tfn receptor expression measured on the cell lines. The exquisite in vitro cytotoxicity of Tfn-abrin variant and Tfn-PE immunotoxins against glioma and melanoma cells warrants further in vivo evaluation and future consideration of these agents for potential clinical application against glioblastoma multiforme and leptomeningeal neoplasia.
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PMID:In vitro efficacy of transferrin-toxin conjugates against glioblastoma multiforme. 131 94

We previously reported that when the oligosaccharide of ganglioside GM1 is covalently attached to cell surface proteins of GM1-deficient rat glioma C6 cells, the cells bind large amounts of cholera toxin (CT) but their cAMP response to CT is not enhanced [Pacuszka, T., & Fishman, P. H. (1990) J. Biol. Chem. 265, 7673-7668]. We now report that when such cells were exposed to CT in the presence of chloroquine, an acidotropic agent, they accumulated cAMP. This raised the possibility that CT bound to cell surface "neoganglioproteins" may be entering the cells through a different pathway from that of CT-bound GM1. To further explore this phenomenon, we covalently attached GM1 oligosaccharide to human transferrin (Tf). The modified protein (GM1OS-Tf) bound with high affinity to Tf receptors on HeLa cells and increased the binding of CT to the cells. The bound CT, however, was unable to activate adenylyl cyclase as measured by cyclic AMP accumulation. By contrast, treatment of HeLa cells with GM1 increased both CT binding and stimulation of cyclic AMP accumulation. Control cells and cells treated with either GM1 or GM1OS-Tf were exposed to CT in the presence of chloroquine. Whereas chloroquine had little or no effect on the response of control or GM1-treated cells to CT, it made the cells treated with GM1OS-Tf responsive to the toxin. Our results indicate that CT bound to its natural receptor GM1 enters the cells through a pathway different from that of toxin bound to neoganglioproteins.
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PMID:Intoxication of cultured cells by cholera toxin: evidence for different pathways when bound to ganglioside GM1 or neoganglioproteins. 131 9

Suramin, a drug used in the treatment of trypanosomiasis and onchocerciasis inhibits growth-factor-induced mitogenesis. We have investigated the effect of suramin on the growth rate and the morphology of C6 glioma cells cultured in the presence of serum or in a serum-free defined medium. Exponentially growing cells were seeded in multi-dish plates (5 x 10(4) cells/2 cm2 well) in DMEM supplemented with 5% fetal calf serum and were continuously exposed to 1 microgram/ml to 1,000 micrograms/ml suramin. Growth rate (determined 9 days after seeding) was reduced by 5%, 33%, 56% and 97%, respectively for suramin concentrations of 1, 10, 100 and 1000 micrograms/ml. Similar results were obtained in serum-free defined medium (DMEM/F12, 1:1, v:v, EGF 5 ng/ml, transferrin 5 micrograms/ml, selenium 10 ng/ml). Moreover, the concentration of suramin in the culture medium remained constant, demonstrating that the drug was not actively metabolized by the cells. Suramin also induced marked changes in cell morphology: the usual bipolar shape of C6 cells evolved toward a more differentiated appearance, with numerous cellular processes allowing a wide number of cell-cell contacts. In parallel, we monitored expression of an adhesion molecule (N-CAM) at both the mRNA and protein levels. Indirect immunofluoresence technique showed an important increase in cell surface N-CAM expression, starting from a dose of 10 micrograms/ml suramin, whereas total cellular content of N-CAM protein as well as its mRNA levels were unaffected. We also observed that the levels of expression of actin and N-CAM mRNAs decreased by a factor of two in cells maintained in defined medium. However, the relative ratio of N-CAM mRNA over actin mRNA was virtually unchanged following suramin treatment. Taken together, our results suggest that suramin (i) exerts a blocking effect of autocrine growth factors, (ii) interferes with the turn-over mechanisms of N-CAM expressed at the cell surface, either by impairing its endocytosis and/or the process of release of the N-CAM 120 isoform.
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PMID:Suramin inhibits proliferation of rat glioma cells and alters N-CAM cell surface expression. 230 43

We have previously shown by immunocytochemistry in rat primary glial cultures that transferrin (Tf) is an early developmental marker for oligodendrocytes. The present work addresses the issue of Tf gene expression and synthesis by neural cells in vitro. For this purpose, we used rat embryonic neuronal cultures and newborn glial cultures of astrocytes and oligodendrocytes. Cultured fibroblasts and C6 glioma cells were used as negative controls. We found that Tf mRNA is present in oligodendrocytes, astrocytes, and neurons. However, oligodendrocytes and astrocytes, but not neurons, were shown to synthesize and secrete Tf. Neither fibroblasts nor C6 glioma cells expressed detectable amounts of Tf mRNA. Tf mRNA levels in astrocyte cultures appeared to be under hormonal control since hydrocortisone markedly reduced message levels. These results show that both astrocytes and oligodendrocytes can synthesize and secrete Tf under cell culture conditions. However, epigenetic factors, such as hydrocortisone, may repress the expression of Tf in astrocytes in vivo.
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PMID:Transferrin gene expression and secretion by rat brain cells in vitro. 235 92

The growth of C6 glioma and L1210 leukemic cells has been stimulated in serum-free medium by the addition or iron or transferrin. The growth promoting action of transferrin was lost when iron was chelated in the culture medium using desferrioxamine. L1210 cells can be grown continuously in serum-free medium supplemented with transferrin or FeCl3 only. In this latter case, it has been shown that L1210 cells secrete into the medium some factor which facilitates iron uptake. The growth of L1210 cells in their exponential phase was blocked by desferrioxamine at the G1-S interface of the cell cycle. The action of transferrin on cell growth was also inhibited by propyl gallate - a known antioxidant which prevents lipid peroxidation. The action of iron was more potent than hemin in reversing the influence of propyl gallate on L1210 cell growth. Iron was found to activate purified guanylate cyclase in the presence of unsaturated fatty acids. This suggests that cyclic GMP synthesis could be involved in the promotion of transformed cell growth by iron.
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PMID:Growth promotion of transformed cells by iron in serum-free culture. 285 72

Several anti-human glioma cytotoxic conjugates were studied in vitro. Monoclonal antibodies (MAbs) to the GE2 glioma-associated antigen (anti-GE 2) and MAbs to HLA-DR antigens (D1/12) or human diferric transferrin (Tfn) were linked to the potent cytotoxin ricin (anti-GE 2-ricin) or to its A subunit (anti-GE 2-RTA, D1/12-RTA, Tfn-RTA). Anti-GE 2-RTA had low cytotoxic activity in both the absence and the presence of lysosomotropic substances inhibiting intracellular degradation. Anti-GE 2-ricin was about 1,000 times more toxic than RTA alone, but showed only 14-fold target specificity. D1/12-RTA was about 20 times more toxic than RTA and its cytotoxic effect increased about 6- to 7-fold when cell-surface HLA-DR antigen expression was enhanced by IFN-gamma treatment. Human diferric Tfn linked to RTA demonstrated the highest cytotoxic activity, being about 5,000 times more toxic than RTA alone for glioma cells and about 6,000 times more toxic for Jurkat cells in the presence of the carboxylic ionofore monensin. Ricin toxin was only about 5 times more toxic for Jurkat and glioma cells than Tfn-RTA-monensin. Tfn-RTA was over 100,000 times more potent than the chemotherapeutic agent BCNU in reducing glioma cell survival in vitro. Addition of 80% human pooled cerebrospinal fluid (CSF) reduced Tfn-RTA toxicity about 10-fold. Kinetics of Tfn-RTA cytotoxicity at non-saturating concentrations indicated that over 80% of target cells could be killed within 8-10 hr in the absence and within 10-12 hr in the presence of human pooled CSF.
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PMID:Sensitivity of human glioma cells to cytotoxic heteroconjugates. 313 94

We have investigated the phenotype of seven human glioma cell lines established in vitro from primary tumour explants. Indirect immunofluorescence and flow cytofluorimetry revealed a heterogeneous distribution of surface GE 2 and CG 12 Tumour Associated Antigens (TAA). In one group of cell lines TAA were detected both at the cell surface and in the cytosol, whereas in a second group of glioma cell lines TAA were found only in the cytosol. We have also investigated the sensitivity of glioma-derived cell lines to antibody-toxin and ligand-toxin conjugates (Immunotoxins). Monoclonal antibodies anti GE 2 antigen linked to ricin toxin A subunit (RTA) showed poor cytotoxicity, which increased about 50 fold when the whole toxin was linked to anti GE 2 monoclonals. Treatment with human recombinant interferon gamma (IFN-gamma) greatly augmented the percentage of HLA-DR+ cells and the amount of HLA-DR antigens per cell. IFN-gamma treatment resulted in a net increase of sensitivity to anti HLA-DR Immunotoxins (IT). Human diferric transferrin linked to RTA exhibited a potent cytotoxic effect against human glioma-derived cells when used in the presence of the lysosomotropic carboxylic ionophore monensin.
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PMID:Human glioma cell lines: tumour associated antigens distribution and sensitivity to antibody-toxin or ligand-toxin conjugates. A preliminary report. 326 95

A new 111In-bleomycin complex (111In-BLMC) is here reported. Its radiochemical purity was 99% by thin-layer chromatography (TLC) (Rf 0.65) and in 5% agarose gel electrophoresis in 0.02 M NaHCO3 it migrated toward the anode. Autoradiographs of TLC and gel electrophoresis plates showed no change on storage for 3 weeks. Urine and plasma from untreated or glioma-bearing mice after injection of 111In-BLMC were analyzed by TLC and gel electrophoresis. Results indicated stability in vivo, nonbinding to transferrin, affinity to viable tumor, and excretion faster than 111In-BLM-B2, 111In-BLM, or 57Co-BLM. Tissue distributions 24 hr after injection of radiopharmaceutical showed activity ratios of tumor to blood, muscle, and brain of 13.1, 12.4, and 81.6, respectively, which were significantly higher than those for previously prepared 111In-BLM-B2 or 111In-BLM (except for brain, 0.05 less than P less than 0.1). The new 111In-BLM complex may be useful in clinical imaging and for combining radionuclide radiotherapy and chemotherapy.
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PMID:A new 111In-bleomycin complex for tumor imaging: preparation, stability, and distribution in glioma-bearing mice. 619 22

We have found a new 111In-bleomycin complex (BLMC), which has high affinity to tumor, does not bind to transferrin and is stable in vivo. Distribution in animals bearing glioma, hepatoma, or mammary adenocarcinoma at 48 hours showed: the ratios of tumor to blood, brain, heart, lung, liver, pancreas, stomach, and femur were 1.4-22.4 times as high for 111In-BLMC as for 67Ga-citrate. In mammary adenocarcinoma, 111In-BLMC bound more to viable and 57Co-Bleomycin (BLM) more to necrotic tumor. In viable tumor, the concentration of 111In-BLMC was similar to that of 57Co-BLM. The ratios of tumor to stomach and pancreas were higher, to blood, brain, muscle, heart, and femur were lower for 111In-BLMC than those for 57Co-BLM. The ratios of tumor to lung, liver, spleen, skin, and kidney were similar for the two compounds. Tumors were imaged more distinctly with the new 111In-BLMC and 57Co-BLM than with 67Ga-citrate. 111In-BLMC is promising for tumor imaging.
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PMID:A new tumor imaging agent--111In-bleomycin complex. Comparison with 67Ga-citrate and 57Co-bleomycin in tumor-bearing animals. 620 27

A serum-free defined medium has been formulated that supports proliferation and morphologic differentiation of U-251 MGsp human and C6-2BD rat glioma cells. This defined medium consists of a basal medium supplemented with transferrin, fibroblast growth factor, hydrocortisone, selenium, biotin, and fibronectin (G2 medium). When U-251 cells were plated in G2 medium on poly-D-lysine precoated dishes, their growth rate was 77% and final cell density was 82% of serum-grown counterparts. The growth rate of C6 cells in G2 medium was 67% compared to cells cultured in serum supplemented medium. Although G2 medium supported the growth of human and rat glioma cells, LA-N-1 human neuroblastoma and WI-38 human fibroblast cells showed no increase in cell number when grown in G2 medium compared to basal medium. A similar formulation (G3 medium), lacking fibroblast growth factor and hydrocortisone, supported the proliferation of RN-22 rat schwannoma cells. Morphologic differences were observed between cells grown in the presence of serum and in defined media. All three glial cell lines changed from a flattened shape in serum supplemented medium to a more spherical appearance in defined medium. In addition, both U-251 and C6 cells developed numerous processes, some reaching several cell diameters in length. These defined media will facilitate studies of the growth and differentiation of glial-derived cells.
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PMID:Proliferation of glial-derived cells in defined media. 621 93


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