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 monoclonal antibody Ki-67 recognizes a nuclear antigen expressed in the G1, S, G2, and M phase of the cell cycle and has been used extensively as an indicator of cellular proliferation in malignant gliomas, both in the laboratory and clinically. Recently, protein kinase C (PKC) inhibitors have been demonstrated to inhibit malignant glioma growth both in in vitro and in vivo. This study was undertaken to determine whether Ki-67 could function as an indicator of cellular proliferation rate after PKC inhibition in gliomas and to explore cell cycle specificity of such inhibition. Both established and low-passage malignant glioma cell lines have previously been shown to be sensitive to growth inhibition by the PKC inhibitors staurosporine and tamoxifen in vitro (IC50 in the nanomolar and micromolar ranges, respectively), as measured by cell numbers, [3H]thymidine uptake, and flow-cytometric DNA analysis. However, in the same cells that are inhibited by staurosporine and tamoxifen on these assays, and on the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay in the present study, the Ki-67 labeling index paradoxically increased in a dose-related manner with the same treatments, as measured by immunohistochemistry and confirmed by flow cytometry. For example, in established line U-87, a 20.5% decrease in thymidine uptake and a 28.5% decrease in absorbance on the MTT assay produced by tamoxifen at 1 microM was associated with an increase in Ki-67 labeling from 42% to 62%; staurosporine, which produces a 78.8% decrease in thymidine uptake in cell line A-172 at 10 nM, produced an increase in Ki-67 labeling from 19% to 32%. In this regard, Ki-67 labeling of glioblastoma tissue from a patient treated with high-dose tamoxifen yielded results within the range of 10% to 15% (consistent with values seen in untreated glioblastoma), despite tumor regression with treatment. The authors' interpretation of these results is that these PKC inhibitors are halting the cell cycle in the G1 phase or the G1-S transition (beyond G0 but before S-phase), resulting in a paradoxical increase in labeling while arresting growth. Two important implications from these observations are that Ki-67 is not a reliable indicator of cellular proliferation after treatment with PKC inhibitors and that these inhibitors used at the doses given above halt cell growth in a phase-specific manner.
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PMID:Paradoxical elevation of Ki-67 labeling with protein kinase inhibition in malignant gliomas. 786 Dec 25

Estramustine is an estradiol-based agent that accumulates in cells containing estramustine binding protein. Previous studies have shown that this binding site is expressed in human glioblastoma cells and that estramustine accumulates in glioma cells, resulting in a concentration-dependent inhibition of proliferation. We have shown that estramustine treatment results in a rapid inhibition of deoxyribonucleic acid synthesis (within 4 h) in human glioblastoma cells associated with an alteration of cell size and shape, consistent with its known antimicrotubule activity. To extend these findings, we performed an immunohistochemical analysis of microtubules with a monoclonal antibody to beta-tubulin, using a colorimetric assay with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to measure the antimitotic effects of estramustine on both human glioblastoma and astrocyte cultures. Within 4 hours, estramustine (10 mumol/L) caused a dramatic alteration in the tubulin staining in glioma cells, characterized by a disorganization in microtubules. Cell shape and microtubule staining in astrocytes were relatively preserved. Estramustine had a concentration-dependent cytotoxic effect in tumor cultures, whereas it had no effect on astrocyte viability at any concentration. Differences in the antimitotic effects do not appear to be related to variations in proliferation rates among these different types of cells. These data suggest that although estramustine is a potent inhibitor of proliferation in glioblastoma cells, it has modest antiproliferative effects on astrocytes and its selective activity is closely correlated with its antimicrotubule properties.
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PMID:Selective antimitotic effects of estramustine correlate with its antimicrotubule properties on glioblastoma and astrocytes. 805 84

Gene transfer with vectors derived from murine retroviruses is restricted to cells which are proliferating and synthesizing DNA at the time of infection. This suggests that retroviral-mediated gene transfer might permit targeting of gene integration into malignant cells in organs composed mainly of quiescent nonproliferating cells, such as in the brain. Accordingly, selective introduction of genes encoding for susceptibility to otherwise nontoxic drugs ("suicide" genes) into proliferating brain tumors may be used to treat this cancer. We investigated the efficacy and dynamics of in vivo transduction of growing brain tumors with the herpes simplex-thymidine kinase gene followed by administration of the antiviral drug ganciclovir. Ganciclovir is phosphorylated by thymidine kinase to toxic triphosphates that interfere with DNA synthesis, resulting in the preferential death of the transduced tumor cells. Rats inoculated with 4 x 10(4) 9L gliosarcoma cells into the frontal lobe were treated 7 days later with an intratumoral stereotaxic injection of murine fibroblasts (NIH 3T3 cells) that were producing a retroviral vector containing the herpes simplex-thymidine kinase gene. Controls received vector producer and nonproducer NIH 3T3 cell lines containing the Escherichia coli lacZ (beta-galactosidase) gene as well as nonproducer NIH 3T3 cells containing the thymidine kinase gene. The animals were rested for 7 days to allow time for in situ transduction of the proliferating tumor cells with the herpes-thymidine kinase retroviral vector. The animals were then treated with ganciclovir, 15 mg/kg i.p. twice a day for 14 days. Gliomas receiving an injection of 3-5 x 10(6) thymidine kinase producer cells regressed completely in 23 of 30 rats given ganciclovir therapy, while 25 of 26 control rats developed large tumors. Intratumoral injection of a lower concentration of thymidine kinase vector producer cells (1.8 x 10(6)) resulted in a lower frequency of tumor regression (5 of 13 rats). To estimate the efficiency of in vivo gene transfer, 9L brain tumors were given injections of 5 x 10(6) beta-galactosidase vector producer cells. 5-Bromo-4-chloro-3-indolyl-beta-D-galactopyranaside staining revealed maximal staining of beta-galactosidase within the tumor 7-14 days after injection of the vector producer cells. In vivo transduction rates in harvested tumors ranged from 10 to 70%. There was no evidence of transduction of the surrounding normal neural tissue. Occasional blood vessel endothelial cells within or adjacent to the tumor were observed to be 5-bromo-4- chloro-3-indolyl-beta-D-galactopyranaside positive.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. 803 19

The present study was undertaken to explore the role of the Protein Kinase C (PKC) signal transduction system in growth regulation of pituitary adenomas. Primary tumor cultures were plated from fresh surgical tumor specimens. The PKC inhibitors Staurosporine and Tamoxifen were added at varying dosages to the cell cultures. Measurements of cell proliferation were performed by [3H]-thymidine uptake and the [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] (MTT) assay. After a 48 h treatment period, both [3H]-thymidine uptake and absorbance on the MTT assay decreased in a dose-related manner in both the staurosporine and tamoxifen-treated cultures (IC50 of 10 nM and 30 microM respectively). Direct measurement of PKC activity using an in vitro assay revealed very high activity (range of 1465-5708 pmol/min/mg protein; within the range previously published for malignant glioma specimens) in 12 frozen specimens of pituitary adenomas (9 nonfunctional adenomas, 1 prolactinoma, 1 gonadotrophin-secreting and 1 corticotroph-secreting adenoma). In contrast, PKC activity measured in normal adenohypophysis was comparatively very low. These data indicate that pituitary adenoma cells display high PKC activity and are sensitive to growth inhibition by PKC inhibitors. These data suggest a role for the PKC system in regulating pituitary tumor growth, which may have implications for future therapy of these tumors.
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PMID:Protein kinase C and growth regulation of pituitary adenomas. 873 88

Previous work has demonstrated the importance of protein kinase C in regulating glioma cell proliferation in vitro. Tamoxifen, a protein kinase C inhibitor when administered in high dosages, is currently being used as an adjuvant in the treatment of patients with malignant gliomas. The patient in the present study harbored a left frontal anaplastic astrocytoma adjacent to Broca's area and the paracentral region, which limited gross resection. After a subtotal resection of the tumor and after radiation, the patient was administered high-dose tamoxifen therapy for gross residual gadolinium-enhancing regions that were revealed by magnetic resonance imaging and by high glucose uptake as demonstrated by positron emission tomography. After treatment, a decrease in gadolinium enhancement on magnetic resonance images and a decrease in glucose uptake revealed by positron emission tomography were noted. A laboratory examination of the tissue obtained from the original surgical resection revealed resistance to radiation therapy but sensitivity to tamoxifen as measured by 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide assay. The subsequent in vitro testing of the tumor that was removed after the recurrence of tumor (22 months after the initiation of tamoxifen) revealed loss of sensitivity to tamoxifen. However, the recurrent tumor remained sensitive to growth inhibition by the potent protein kinase C inhibitor, hypericin, despite loss of sensitivity to tamoxifen in vitro, suggesting the potential clinical application of this agent. This close in vitro correlation with the clinical course of the patient in the present study suggests a potential role for such in vitro radiation and chemosensitivity testing in designing a rational individualized clinical course of treatment.
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PMID:Malignant glioma sensitivity to radiotherapy, high-dose tamoxifen, and hypericin: corroborating clinical response in vitro: case report. 883 15

Ouabain markedly stimulated not only [3H]thymidine incorporation but also [3H]uridine incorporation into astrocytes. The effects were observed at 36-48 hr and 12-72 hr after addition of ouabain, respectively. The dose-response curves were both bell-shaped types with a peak at 10(-3) M for thymidine incorporation and 2 x 10(-3) M for uridine incorporation. Ouabain increased cell number as determined by an assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and by a method using a hemocytometer. Low concentration of external K+ mimicked the effect of ouabain in stimulating [3H]-thymidine incorporation, and high concentration of external K+ blocked the effect of ouabain. In contrast to astrocytes, ouabain did not stimulate [3H]thymidine incorporation into C6 glioma and fibroblast cells. The effect of ouabain on [3H]thymidine incorporation in astrocytes was dependent on external Ca2+, and it was blocked by cycloheximide. These findings indicate that prolonged Na+, K(+)-ATPase inhibition causes cell proliferation in cultured astrocytes in cell-specific and Ca(2+)-dependent manners.
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PMID:Ouabain-induced cell proliferation in cultured rat astrocytes. 901 43

Three series of new boron-containing spermidine/spermine (SPD/SPM) analogues have been synthesized: N1- and N5-(4-carboranylbutyl) SPD/SPM derivatives (SPD-1, SPD-5, SPM-1, SPM-5); N1,N10-diethyl-N5-(4-carboranylbutyl)spermidine (DESPD-5), N1,N14-diethyl-N5-(4-carboranylbutyl)spermine (DESPM-5); and N5,N10-bis(4-carboranylbutyl)spermine (SPM-5,10). In vitro studies using rat F98 glioma cells have shown that these polyamines retain the ability to displace ethidium bromide from calf thymus DNA and are rapidly taken up by F98 glioma cells. However, their cytotoxicities, especially those with terminal N-substituted (SPD-1, SPM-1) boron compounds, are greater than those of SPD/SPM. Nevertheless, the groundwork has been created for a new class of boron-containing compounds that maybe useful for boron neutron capture therapy of tumors.
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PMID:Boron-containing polyamines as DNA targeting agents for neutron capture therapy of brain tumors: synthesis and biological evaluation. 939 69

Binding and toxicity of boronated phenanthridinium analogues were studied in vitro using cultured human malignant glioma cells. The compounds, 5-ortho- (5-o-CP), 5-para- (5-p-CP), 5-nido- (5-n-CP) and 6-nido-carboranyl phenanthridinium (6-n-CP) showed varying toxic effects. The cells were exposed to the compounds for 2 or 24 h. The span between non-toxic and toxic concentrations seemed to be very narrow. 5-p-CP was the most toxic compound, causing total cell death at a concentration of 5 micrograms/ml cell culture medium. None of the compounds showed toxic effects at a concentration of 1 microgram/ml. Viable cells incubated with the compounds at this concentration showed a > 100-fold accumulation of boron. Only approximately 1/4 of this accumulation was found in cells permeabilized and inactivated with acetone. Fluorescent images of acetone-treated cells showed clear uptake of the compounds in the cell nucleus, as for ethidium bromide, while for viable cells binding to structures other than DNA was also observed. These results were confirmed by subcellular boron determination. All tested compounds intercalate into DNA, as was demonstrated in cell-free systems with calf thymus DNA. The hypothesis is that the compounds are trapped in the cellular membranes of viable cells because of their lipophilicity, before reaching nuclear DNA.
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PMID:Cytotoxicity and subcellular localization of boronated phenanthridinium analogues. 944 6

This study concerns the use of the MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] colorimetric assay to evaluate the chemosensitivity of the C6 rat glioma cell line to a panel of twelve chemotherapeutic agents. In a previous study of in vitro chemosensitivity of human glioma cell lines, the present authors found a range of sensitivities of the respective cell lines to a panel of chemotherapeutic agents [1]. We then devised an experimental strategy to begin an in vivo evaluation of the correlation between in vitro chemosensitivity and clinical response in an in vivo animal model, such as the model employing the C6 rat glioma cell line. As a step towards utilizing the C6 rat glioma in vivo model, we carried out the present study (Part 1) to determine the correspondence between chemosensitivity to human glioma cell lines and the rat C6 glioma cell line. If a correspondence were to be found, this would enable experimental use of the C6 tumor model for in vivo testing of chemotherapeutic agents. As reported in this paper (Part 1), a correspondence was found, suggesting that the C6 rat glioma represents a suitable model of human glioma for chemotherapeutic studies. This finding served as a basis for proceeding with an in vivo study of chemotherapeutic efficacy which is the subject of a companion report [2].
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PMID:Chemotherapy in experimental brain tumor, part 1: in vitro colorimetric MTT assay. 952 20

Previous work in our laboratory has shown a correspondence between the chemosensitivity of C6 rat glioma and that of human glioblastoma (GBM) to a panel of chemotherapeutic agents in vitro, as determined by the MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] colorimetric assay. In the present study, an in vivo model of intracerebral C6 glioma in Sprague-Dawley rats was used to determine if a correlation exists between in vitro chemosensitivity and in vivo survival of the animals, and post-mortem histopathological changes in the tumor. Cisplatin (CDDP) and methotrexate (MTX), agents previously shown to demonstrate high and low in vitro cytotoxicity, respectively, against C6, were administered by intra-carotid infusion over the course of two days. In a separate series of animals, LTC4 was administered prior to infusion of CDDP or MTX; LTC4 was used in view of its known, selective, vasogenic effect on the permeability of brain tumor capillaries. It was found that survival of animals treated with CDDP alone was increased, although this did not reach statistical significance; histopathologically, CDDP-treated animals showed significant tumor necrosis. However, in CDDP-treated animals, pre-treatment with LTC4 increased survival to a statistically significant degree. When administered alone, LTC4 (not followed by CDDP) had no effect on either survival or histology. The survival-enhancing effect of CDDP, when combined with LTC4, was probably not due to any cytotoxic effect of LTC4; this is based on our finding that, on the in vitro MTT colorimetric assay, LTC4 showed low cytotoxicity for C6 glioma cells. By contrast with CDDP, MTX -- with or without pretreatment with LTC4 -- affected neither survival nor tumor histology. With respect to the question of correspondence between the MTT colorimetric in vitro assay and in vivo effect, MTX showed a clear correlation: low cytotoxicity in vitro and poor in vivo response. In the case of CDDP, the correspondence was not clear-cut: there was a high level of in vitro chemosensitivity of the C6 cell line to CDDP as well as post-mortem tumor necrosis, but in vivo testing showed no significant prolongation of survival. However, pre-treatment with LTC4 did significantly extend survival in animals treated with CDDP.
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PMID:Chemotherapy in experimental brain tumor, part 2: pretreatment with leukotriene C4 prolongs survival. 952 21


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