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)

The overexpression of the multidrug resistance (mdr1) gene and its product, P-glycoprotein (P-gp), is thought to limit the successful chemotherapy of human tumours. The mechanism by which mdr1 gene and P-gp are overexpressed in human tumours, however, is not yet clear. In this report, we show that the mdm2 (murine double minute 2) gene induced the expression of the mdr1 gene and P-gp in human glioblastoma U87-MG cells, which did not express the MDM2 protein or P-gp. The mdm2 gene, in addition, conferred the resistance of U87-MG cells to the apoptotic cell death induced by etoposide (VP-16) or doxorubicin. Furthermore, treatment with mdm2 antisense oligonucleotides inhibited the expression of P-gp in MDM2-expressing U87-MG cells. These findings suggest that the mdm2 gene may play an important role in the development of MDR phenotype in human tumours.
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PMID:mdm2 gene mediates the expression of mdr1 gene and P-glycoprotein in a human glioblastoma cell line. 888 15

The overexpression of the multidrug resistance (mdr1) gene and its product, P-glycoprotein (P-gp), is thought to limit the successful chemotherapy of human tumors. Recent studies demonstrate that SN-38, a metabolite of the camptothecin (CPT) derivative CPT-11, has antitumor effects on several tumors, but the mechanisms responsible for its cytotoxicity remain unclear. We therefore determined whether SN-38 has cytotoxic effects on MDR human glioblastoma GB-1 cells and non-MDR human glioblastoma U87-MG cells. Furthermore, we determined what role SN-38 plays in the induction of cytotoxicity in these tumor cells. In this study, we demonstrated that SN-38 had significantly stronger antitumor effects on GB-1 and U-87MG cells than did CPT (P < 0.01 and P < 0.05, respectively). In addition, findings obtained using a DNA fragmentation assay, Hoechst 33258 staining, in situ end-labeling and cell cycle analysis demonstrated that SN-38 induced apoptosis in these tumors. Our results suggest that SN-38 has a stronger antitumor effect on malignant glioma cells regardless of MDR expression than does CPT, and therefore can be considered a new chemotherapeutic agent potentially effective in the treatment of human primary or recurrent malignant gliomas resistant to chemotherapy.
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PMID:Induction of apoptosis in multi-drug resistant (MDR) human glioblastoma cells by SN-38, a metabolite of the camptothecin derivative CPT-11. 905 55

Three-dimensional cell cultures (spheroids) provide an in vitro approximation of solid tumors in vivo. Some mechanisms of drug resistance were reported to differ in their effects on monolayer and spheroid cells. We have compared the effect on the expression of P-glycoprotein (Pgp), the MDR1 gene product, on vinblastine resistance in two glioblastoma lines, U87 and U251, grown as either monolayers or spheroids. U87 cells form spheroids spontaneously and the spheroids continue to grow, while U251 cells form spheroids only when plated over agarose and do not proliferate in spheroids. U87 cells are equally resistant to vinblastine in monolayer and in spheroids, while U251 cells are 4.5 times more resistant in spheroids than in monolayers. The distribution of a fluorescent vinblastine derivative in cells of spheroids was more heterogeneous than in monolayers. MDR1-expressing U87 cells increased their resistance 9-fold in monolayer and 50-fold in spheroids, while MDR1 transduction of U251 cells made them 20-fold more resistant in monolayer and 160-fold more resistant in spheroids. MDR1 expression in both cell lines decreased the accumulation of 3H-vinblastine and fluorescent vinblastine derivative. These results indicate that MDR1 is more efficient in conferring drug resistance in spheroids than in monolayer cells.
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PMID:Drug resistance conferred by MDR1 expression in spheroids formed by glioblastoma cell lines. 941 66

Glioblastoma is the most invasive form of primary brain tumors, and is often refractory to chemotherapy. Herein, we provide evidence that two highly invasive human glioma cell lines U-87 MG and U-373 MG, entered apoptosis after 48 hours following 24 h growth arrest induced by Doxorubicin (10 micrograms/2 x 10(5) cells/ml). Apoptosis depended solely on the level of intracellular drug accumulation, and it was not related to a functional p53 tumor suppressor factor. The multidrug resistance gene 1 (mdr-1) encoded P-glycoprotein (P-gp) was weakly expressed in these cells upon exposure to Doxorubicin, and exerted no influence on the extent of cellular drug efflux. Drug efflux occurred only in U-373 MG glioma cells subsequent to physical damage of the membrane upon exposure to Doxorubicin. Pretreatment of tumor cells with 10 micrograms/ml Doxorubicin precluded tumor formation on the chorioallantoic membrane (CAM) of embryonated hen eggs. Single-dose application of 0.4 microgram Doxorubicin on CAM/U-87 MG and CAM/U-373 MG tumor transplants inhibited tumor invasion in CAM tissue by 40 to 50%. These data suggest that highly invasive glioblastomas can be driven to apoptosis following growth arrest induced by Doxorubicin, providing that intracellular drug accumulation suffices cytotoxic levels.
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PMID:Doxorubicin-induced cell death in highly invasive human gliomas. 1036 37

PURPOSE: This study was undertaken to determine the usefulness of Tc-99m methoxyisobutylisonitrile (MIBI) in brain tumors compared with TI-201 imaging. The authors evaluated the correlation between MIBI uptake and the presence of P-glycoprotein, and also the relation between MIBI uptake in response to combined radiotherapy and chemotherapy in glioblastoma. MATERIALS AND METHODS: Thirty-four brain tumors composed of 15 glioblastoma multiforme (GBM), 5 anaplastic astrocytomas, 5 low-grade astrocytomas, and 9 metastases were evaluated. Early and delayed images were obtained for MIBI and Tl-201 scintigraphy. P-glycoprotein status in all GBM, 2 anaplastic astrocytomas, 2 low-grade astrocytomas, and 2 metastases were evaluated immunohistochemically. Patients with GBM were divided into an effective and a noneffective group according to the change in tumor size. MIBI uptake indices were compared for these two groups. RESULTS: Both radiopharmaceuticals accumulated in all GBM and anaplastic astrocytomas. In low-grade astrocytomas, only one case showed tracer uptake. In metastasis, two cases showed high uptake on early images and marked washout on delayed images. Uptake ratio values (early uptake ratio and delayed uptake ratio) in all tumors were significantly higher in MIBI than in Tl-201. Immunohistochemical studies showed that the metastases were positive for P-glycoprotein but the GBM were not. In low-grade astrocytomas, a few cells were positively stained. In relation to the therapeutic outcome of GBM, both the early and delayed uptake ratios of MIBI were significantly greater in the noneffective group. CONCLUSIONS: Although diagnostic ability was comparable in MIBI and Tl-201, the imaging quality was better in MIBI. Both radiopharmaceuticals are useful in differentiating low-grade glioma from high-grade glioma. MIBI delayed imaging could also reflect the presence of P-glycoprotein. Intense MIBI uptake was also predictive of a poor clinical outcome in GBM.
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PMID:The usefulness of Tc-99m MIBI for evaluating brain tumors: comparative study with Tl-201 and relation with P-glycoprotein 1051 2

The presence of the cellular multidrug resistance (MDR1) gene and its product, P-glycoprotein (Pgp), is thought to be a mechanism for the failure of chemotherapy in cancer patients. Calcium channel blockers have been shown to sensitise cancer cells to anticancer drugs by reversing Pgp expression in cell lines. The interactions between anticancer drugs such as carmustine (BCNU), vincristine (VCR) and procarbazine (PCB) and calcium channel blockers such as nimodipine and verapamil on cultured cells of glioblastoma from eight patients were therefore tested. Pgp expression was examined immunohistochemically using C219 monoclonal antibody in cytospin preparation. The cytotoxicity of the drugs was screened using microculture tetrazolium assay. The cells from five patients showed positive immunoreaction for Pgp. Nimodipine showed growth-inhibitory activity against glioblastoma cells at a rate of 16.55-26.88% (P < 0.05), but a similar effect was not observed with verapamil. While antiproliferative effects of BCNU were around 20.91-45.09% (P < 0.05) on the cells from seven patients, VCR was the most effective agent in inhibition of cell growth at a rate of 26.43-48.47% (P < 0.05). The response of the cells from five patients to PCB was from 11.98 to 16.32% (P < 0.05). When used together, nimodipine further enriched cytotoxicity of the anticancer drugs up to 11.14-40.85% (P < 0.05) without relation to Pgp expression. In conclusion, the enhancement of cytotoxicity of anticancer drugs by nimodipine suggests that there might be a synergy between anticancer drugs and nimodipine in the inhibition of glioma cell growth.
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PMID:The effects of anticancer drugs in combination with nimodipine and verapamil on cultured cells of glioblastoma multiforme. 1062 52

Human malignant gliomas are commonly resistant to chemotherapy. Here, we examined the role of the multidrug resistance (mdr) mechanism in the chemo-resistance of these tumors, using a twofold approach: (i) by assessing a possible mdr phenotype before and after chronic drug exposure of glioma cells in vitro, and (ii) by assessing the modulation of expression of the mdr-associated P-glycoprotein (Pgp) using radiotherapy and serial cycles of chemotherapy in human glioblastoma patients in vivo. T98G, and to a lesser degree, LN-229 human malignant glioma cells exhibit a constitutive mdr phenotype as determined by the modulation of dye transport and by the augmentation of chemosensitivity by the mdr antagonist, verapamil. Thus, coexposure to verapamil enhances the cytotoxicity of vincristine, doxorubicin and VM26 in T98G cells and that of vincristine in LN-229 cells. Chronic exposure of the cells to low concentrations of vincristine and doxorubicin, but not VM26, topotecan or BCNU, moderately enhances the mdr-like phenotype, as assessed by drug expulsion assays. However, chronic exposure to increasing drug concentrations does not significantly alter the sensitivity to the respective drugs. These data are consistent with a constitutive, but not drug-inducible, mdr-like drug resistance in glioma cells in vitro. Immunocytochemical analysis of human malignant gliomas in vivo reveals that Pgp expression is more abundant in endothelial cells within the gliomas, than in the glioma cells proper. Importantly, Pgp expression is unaltered by radiochemotherapy, assessed by comparative immunocytochemistry of glioma specimens obtained serially before and after radiochemotherapy. We conclude that (i) glioma cells exhibit constitutive mdr-like drug resistance that is not significantly altered by chronic drug exposure in vitro; (ii) endothelial cells may play an important role in Pgp-mediated drug resistance of gliomas in vivo; (iii) radiotherapy and repeated chemotherapy cycles do not modulate Pgp expression in human malignant gliomas in vivo; (iv) there is preliminary evidence for a non-Pgp, verapamil-sensitive drug transport activity in glioma cells.
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PMID:Evidence for a constitutive, verapamil-sensitive, non-P-glycoprotein multidrug resistance phenotype in malignant glioma that is unaltered by radiochemotherapy in vivo. 1080 1

N-(pyridin-4-yl)-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid (D-24851) is a novel synthetic compound that was identified in a cell-based screening assay to discover cytotoxic drugs. D-24851 destabilizes microtubules and blocks cell cycle transition specifically at G2-M phase. The binding site of D-24851 does not overlap with the tubulin binding sites of known microtubule-destabilizing agents like vincristine or colchicine. In vitro, D-24851 has potent cytotoxic activity toward a panel of established human tumor cell lines including SKOV3 ovarian cancer, U87 glioblastoma, and ASPC-1 pancreatic cancer cells. In vivo, oral D-24851 treatment induced complete tumor regressions (cures) in rats bearing Yoshida AH13 sarcomas. Of importance is that the administration of curative doses of D-24851 to the animals revealed no systemic toxicity in terms of body weight loss and neurotoxicity in contrast to the administration of paclitaxel or vincristine. Interestingly, multidrug-resistant cell lines generated by vincristine-driven selection or transfection with the Mr 170,000 P-glycoprotein encoding cDNA were rendered resistant toward paclitaxel, vincristine, or doxorubicin but not towards D-24851 when compared with the parental cells. Because of its synthetic nature, its oral applicability, its potent in vitro and in vivo antitumoral activity, its efficacy against multidrug-resistant tumors, and the lack of neurotoxicity, D-24851 may have significant potential for the treatment of various malignancies.
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PMID:D-24851, a novel synthetic microtubule inhibitor, exerts curative antitumoral activity in vivo, shows efficacy toward multidrug-resistant tumor cells, and lacks neurotoxicity. 1119 93

The aim of our study was to investigate the functional expression of P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRPs) in 2 distinct glioma cells (GL15 and 8MG) from patients with glioblastoma multiforme. MDR1 gene and Pgp expression was not detected in either cell line by RT-PCR and Western blotting, respectively. In contrast, MRP1 was detected at both mRNA and protein level in both cell lines, with a higher expression in the 8MG cells that occur predominantly at the cell membrane. Three other MRPs (MRP3, MRP4 and MRP5) were detected by RT-PCR in both cell lines, whereas MRP2 was not expressed. In addition, MRP3 protein was also detected by immunocytochemistry in both GL15 and 8MG cell lines. Indomethacin and probenecid, 2 modulators of MRPs activity, increased the accumulation of vincristine and etoposide, 2 substrates of MRPs, by both cell lines. These modulators also decreased the efflux of vincristine from both cell lines with a more pronounced effect in 8MG cells. In conclusion, our results show functional expression of MRPs leading to a decrease in the intracellular vincristine and etoposide concentrations in human glioblastoma cell lines. Furthermore, our results that exhibit protein expression of MRP1 and MRP3 and gene expression of MRP4 and MRP5 in these 2 glioblastoma cell lines suggest new mechanisms that could lead to a MDR phenotype of tumour cells in patients with glioblastoma multiforme.
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PMID:Molecular and functional MDR1-Pgp and MRPs expression in human glioblastoma multiforme cell lines. 1185 4

The glioblastoma is the highest dedifferentiated form of astrocytic brain tumors, which is refractory to chemotherapy in most cases. The lack of chemotherapeutic success is correlated with overexpression of the product P-glycoprotein (PGP) coded by the multidrug resistance 1 (MDR1) gene and a subsequent release of drugs from the tumor cells. For the chemotherapeutical treatment of glioblastomas, the endothel cell is of special importance since due to its manifold metabolic and protective tasks within the blood-brain barrier, it already has a relatively high PGP expression under physiological conditions. The aim of the present study was to analyze the uptake of the antimitotic drug Doxorubicin (DOX) and the expression of PGP in human and rat glioblastoma cell lines and in a human endothelial cell line at different time points. In the following in vivo approach DOX enriched glioblastoma cells were transplanted into rats and the developed tumor was investigated histologically. The results showed an increased uptake and an enhanced expression of PGP at certain time points in every cell line. In the tissue a DOX release was mainly observed in perivascular surroundings. It was concluded that DOX enhanced the constitutive PGP expression which led to a subsequent exclusion of DOX in tumor cells but also in the endothelial cells of the tumor vasculature. Since the vascularization is a prerequisite for tumor growth, the inhibition of the PGP expression in tumor endothelial cells might be a clinical approach to make the DOX treatment more effective.
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PMID:Repetitive doxorubicin treatment of glioblastoma enhances the PGP expression--a special role for endothelial cells. 1294 Jun 27


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