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)

Estramustine, an estradiol-17 beta and nornitrogen mustard complex, is used in the treatment of advanced prostatic carcinoma. A specific estramustine binding protein (EMBP) is important for its cytotoxic action, and the presence of EMBP has previously been demonstrated in rat and human prostatic cancer tissue. Significant levels of EMBP were detected by radioimmunoassay in human brain-tumor tissue. The EMBP concentrations (expressed as ng/mg protein) in 16 astrocytomas (mean 2.6 ng/mg, range 0.5 to 6.2 ng/mg) and seven meningiomas (mean 5.1 ng/mg, range 0.3 to 9.3 ng/mg) were significantly higher than that found in four samples of epileptic brain (mean 0.7 ng/mg, range 0.5 to 1 ng/mg) and 18 samples of normal brain (mean 0.5 ng/mg, range 0.2 to 1.0 ng/mg). The uptake, metabolism, and antiproliferative effects of the prostatic anticancer agent estramustine have been previously demonstrated in cultured glioma cells. The presence of EMBP may suggest a selective binding and effectiveness in human brain-tumor tissue.
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PMID:Estramustine binding protein in human brain-tumor tissue. 170 87

Estramustine, a conjugate of estradiol-17 beta and nor-nitrogen mustard currently used in prostatic cancer, was found to exert a dose-dependent antiproliferative effect on the human malignant glioma cell lines U-251 MG and U-105 MG. At equimolar concentrations the inhibitory effects of the estramustine complex were clearly more pronounced than those of estradiol and nor-nitrogen mustard given alone or in combination. Flow cytometric analyses support the concept that estramustine cytotoxicity is mediated via separate mechanisms. The intact estramustine complex may be important for effects related to microtubule function which add to the cytotoxic potential of the alkylating component.
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PMID:Effects of estramustine and its constituents on human malignant glioma cells. 236 85

Estramustine-phosphate (EMP), a combination of nornitrogen mustard and 17 beta-estradiol, has been demonstrated to exert specific antiproliferative effects on human glioma cells in vitro. The cytotoxic effect is, at least partially, mediated by inhibiting microtubule function. In this study the combined effect of EMP and radiation was evaluated in the human glioma cell-lines, 251-MG and 105-MG, in vitro, and in the rat glioma BT4C in vitro and in vivo. In all cell-lines an additive effect of EMP and radiation was obtained in vitro. Assuming equal effect of EMP is obtained in subsequent radiation fractions, the cell kill will be increased from 2-3 to 5-10 logs if delivering 30 fractions of 2 Gy combined with EMP. In the BT4C rat model the combined effect was found to be synergistic. Flow cytometry demonstrated an arrest in G2/M phase in all cell-lines after EMP treatment. This block in G2/M phase in addition to the previously demonstrated induction of free oxygen radicals, and the increase of blood flow with an assumed subsequent increase of oxygenation, might provide an explanation for the observed radiosensitizing effect of estramustine.
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PMID:Radiosensitizing effect of estramustine in malignant glioma in vitro and in vivo. 767 81

Estramustine, a combination of 17 beta-oestradiol and nor-nitrogen mustard, has been shown to be metabolised and to induce specific antiproliferative effects in malignant glioma, including arrest of glioma cells in the G2/M phase of the cell cycle, damage to cell membranes and DNA and induction of free oxygen radicals. To evaluate further the effects of estramustine, an in vivo rat glioma model using inbred BD-IX rats and the BT4C cell line was set up. In order to detect cells with fragmented DNA, tumour and brain specimens were, following fixation for histological examination, processed for in situ end labelling (ISEL) with biotin-labelled nucleotides. Fresh tissue fragments were also used for DNA integrity analysis on agarose gels. It was demonstrated that estramustine induced clusters of ISEL-positive cells and a pronounced typical fragmentation of DNA 0.5-8 h after treatment. In tumours examined 24 or 94 h after estramustine treatment, and in untreated tumours, only occasional single ISEL-positive cells were scattered in the tumour. DNA from normal brain tissue did not display any visible sign of fragmentation. These changes are indicative of programmed cell death induced by estramustine in glioma cells but not in normal brain tissue. Further studies are, however, needed to establish in detail the mechanism of cell death following treatment with the antimitotic drug estramustine.
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PMID:DNA fragmentation induced by the antimitotic drug estramustine in malignant rat glioma but not in normal brain--suggesting an apoptotic cell death. 771 Sep 34

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

Estramustine-binding protein (EMBP) is a M(r) 46,000 heterodimeric protein originally isolated from prostatic tissue. It has a demonstrated high affinity for, and selective binding of, estramustine, which is a derivative of 17 beta-estradiol and nornitrogen mustard with antimitotic activity. In this study, we have analysed the expression of an EMBP-like protein in astrocytoma specimens. Immunohistochemistry revealed a pronounced reactivity for EMBP in astrocytoma grades III-IV as well as in metastatic prostatic adenocarcinoma used as positive control. In astrocytoma grades I-II, the expression was weak. The EMBP-like protein was quantified by radioimmunoassay in astrocytoma tumor tissue with higher concentrations in malignant astrocytoma, grades III-IV, compared to grades I-II tumors. Western immunoblotting of immunoaffinity purified EMBP-like protein under nonreducing conditions revealed an immunoreactivity corresponding to M(r) 138,000 and 200,000, indicating a different structure of EMBP in astrocytoma compared to prostatic tissue. Specific binding and the presence of saturable binding sites for 3H-labeled estramustine were demonstrated in astrocytoma tissues expressing EMBP-like protein. Scatchard plot analysis showed a Kd at approximately 30 nM, which suggests a binding affinity for estramustine in the same range as previously reported for EMBP in the prostate. Moreover, the number of estramustine binding sites/g tumor as calculated from the Scatchard plots was well correlated with the EMBP levels determined in the radioimmunoassay. In conclusion, an EMBP-like protein is expressed in astrocytoma. This protein may be responsible for the specific binding of estramustine in the tumor tissue. Whether this specific binding of estramustine is of importance for the cytotoxic effect in glioma cells remains to be evaluated.
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PMID:Estramustine-binding protein and specific binding of the anti-mitotic compound estramustine in astrocytoma. 806 65

Estramustine is an estradiol-based antimicrotubule agent that accumulates in malignant glioma cells, resulting in a concentration-dependent inhibition of proliferation. This agent has been shown to synchronize human glioma cells at G2-M consistent with its known effects on the mitotic spindle and potentially could be used as a radiation enhancer. We determined the effects of estramustine on the cell cycle of glioblastoma cells by flow cytometry. These findings were compared with clonogenic survival in cells pretreated with varying concentrations of estramustine prior to irradiation. These experiments indicated that 24 h treatment with 1 microM estramustine had no effect on the percentage of G2-M cells and did not enhance the cytotoxic effects of radiation while 10 microM estramustine increased the G2-M fraction by 100% associated with a potentiation factor as high as 8.5 and a relative radiation sensitivity at 70% cytotoxicity of 5.2 compared with 15.4 for control cells. Estramustine can be administered p.o. on a daily schedule with minimal systemic toxicity. These data suggest that estramustine may be an effective radiation enhancer for glioblastoma.
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PMID:Estramustine sensitizes human glioblastoma cells to irradiation. 813 40

Estramustine is an estradiol-based agent that has been shown to accumulate in human glioma cells, resulting in a concentration-dependent alteration in cell size and shape within minutes and an inhibition of proliferation over 3 to 6 days. We evaluated human glioblastoma cultures with [3H]thymidine incorporation assays to determine estramustine's early effects on deoxyribonucleic acid synthesis in these tumors. Because estramustine shares a common structural motif with other antimicrotubule drugs, we synthesized four A-ring conjugates of estrone that contained a carbamate moiety but lacked nitrogen mustard. These analogs were examined by [3H]thymidine incorporation and compared with vinblastine. Greater than 70% inhibition of [3H]thymidine incorporation occurred within 1 hour of treatment with estramustine at 10(-5) mol/L, which increased to 80% inhibition at 4 hours. Ethyl carbamate JE208 was nearly as effective as estramustine in inhibiting deoxyribonucleic acid synthesis, and both were more effective than vinblastine. The inhibitory effects of estramustine and estrone analogs were reversible; vinblastine was not reversible. Although estramustine and JE208 induced similar antiproliferative and morphological changes in glioblastoma cells that persisted for at least 4 days, there was a modest recovery of morphology and thymidine incorporation with JE208 after prolonged treatment. The common findings with estramustine and JE208 suggest that these agents may have a similar mechanism of action and form the basis for the investigation of new agents that may rapidly and reversibly inhibit glioblastoma.
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PMID:Estramustine and estrone analogs rapidly and reversibly inhibit deoxyribonucleic acid synthesis and alter morphology in cultured human glioblastoma cells. 838 27

Estramustine, a carbamate ester combining 17 beta-estradiol and nornitrogen mustard, has primarily been employed in the treatment of advanced prostatic carcinoma. However, a significant amount of preclinical investigation has been directed toward estramustine's activity against human malignant glioma. These studies have demonstrated that estramustine has potent antiproliferative effects against malignant glioma both in vitro and in vivo. Similar antimitotic effects also have been demonstrated for other carbamate esters. Estramustine does not impair proliferation of nonneoplastic astrocytes at concentrations that inhibit glioma cells. Although the reasons for this selective activity remain to be determined, it has been shown that malignant gliomas expresses an estramustine-specific binding site, estramustine-binding protein, more than brain tissue. In the clinical situation, an uptake and accumulation of estramustine in human glioma tissue have been demonstrated. Estramustine has been shown to enhance the cytotoxic effects of irradiation in relatively radioresistant glioma cells both in cell culture and in a rat glioma model. Estramustine has been regarded as mainly an anti-mitotic drug but recently other effects such as inhibition of DNA synthesis, induction of apoptosis, and membrane alterations have been shown. This report summarizes the preclinical observations concerning the effects of estramustine and related compounds on human malignant gliomas. These findings form the basis for proposing further laboratory and clinical investigation regarding estramustine and human malignant gliomas.
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PMID:Estramustine in malignant glioma. 886 6

Estramustine (EaM), a carbamate ester of 17beta-estradiol and nor-nitrogen mustard, is a cytotoxic compound with antitumoral effect in malignant glioma in vitro and in vivo . However, knowledge of the pharmacokinetics of EaM in experimental glioma is limited. The objective of this study was therefore to investigate further the distribution of EaM in the BT4C rat glioma model. Assessment of EaM uptake and distribution was performed by quantitative whole-body autoradiography. In addition, the uptake of EaM and its metabolites estromustine (EoM), estradiol, and estrone were analyzed by gas chromatography. EaM was taken up from the circulation and was found to be the main product in glioma tissue. Whole-body autoradiography after [14C]-EaM administration revealed a strong 14C label simultaneously in tumor and normal brain tissue at 0.5 h after drug administration. In tumor tissue, sustained high levels of 14C label were detected at 12 h after drug administration. In contrast to the tumor, radioactivity in normal brain tissue rapidly leveled off, indicating a retention of radioactivity in the tumor. The tumor/brain radioactivity ratio reached a peak of 4.5 at 12 h after drug administration. High levels of 14C label were also found in pulmonary tissue. By gas chromatography, EoM was found to be the main metabolite in plasma. However, EaM reached higher levels in tumor tissue, with the mean tumor/plasma ratio being 11.7 as compared with 2.0 for EoM. Only low plasma levels of the estrogen metabolites were detected. In conclusion, EaM is taken up in the BT4C rat glioma tissue and is retained in the tumor as compared with normal brain tissue and plasma. EaM showed a greater selectivity for tumor tissue, exhibiting a high tumor/plasma ratio as compared with EoM. The distribution pattern after administration of EaM, as evaluated by both whole-body autoradiography and gas chromatography, supports the earlier suggestion that the uptake is related to a protein with EaM-binding characteristics.
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PMID:Distribution of estramustine in the BT4C rat glioma model. 948 1


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