Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Tyrosinase-related protein (TRP)-2 is not only expressed on glioma cells, but is naturally processed and presented by their surface MHC molecules and is recognized by TRP-2-specific cytotoxic T cells. After active immunotherapy, we detected TRP-2-specific cytotoxic T lymphocyte (CTL) activity in patients' peripheral blood mononuclear cells (PBMC). Tumor cells from postvaccination resections showed significantly lower TRP-2 expression and higher sensitivity to carboplatin and temozolomide than those autologous cell lines from prevaccination resections in two patients who demonstrated CTL response to TRP-2. One of two patients underwent treatment with temozolomide after recurrence and responded dramatically. TRP-2-transfected cell line (TRP-2-U373) resulted in significant drug resistance to carboplatin and temozolomide compared to wild-type U-373 (W-U373). There was no significant difference, however, in the mRNA expression of other common drug resistance related proteins, such as BCRP-1, MGMT, MDR-1, MRP-1 and MRP-3, after TRP-2 transfection. TRP-2-U373 tumor cells were immunoselected by a TRP-2-specific CTL line. The immunoselected cells (IS-TRP-2-U373) demonstrated significantly increased sensitivity to carboplatin and temozolomide compared to TRP-2-U373. For the first time, we provide evidence that immunological targeting of tumor-associated antigen TRP-2 significantly increases sensitivity to chemotherapy.
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PMID:Cytotoxic T cell targeting of TRP-2 sensitizes human malignant glioma to chemotherapy. 1589 11

Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children.
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PMID:Dose finding and O6-alkylguanine-DNA alkyltransferase study of cisplatin combined with temozolomide in paediatric solid malignancies. 1613 28

Alkylating agents, such as temozolomide, are among the most effective cytotoxic agents used for malignant gliomas, but responses remain very poor. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) plays an important role in cellular resistance to alkylating agents. IFN-beta can act as a drug sensitizer, enhancing toxicity against a variety of neoplasias, and is widely used in combination with other antitumor agents such as nitrosoureas. Here, we show that IFN-beta sensitizes glioma cells that harbor the unmethylated MGMT promoter and are resistant to temozolomide. By means of oligonucleotide microarray and RNA interference, we reveal that the sensitizing effect of IFN-beta was possibly due to attenuation of MGMT expression via induction of the protein p53. Our study suggests that clinical efficacy of temozolomide might be improved by combination with IFN-beta using appropriate doses and schedules of administration.
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PMID:IFN-beta down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide. 2797 4

Forty-two patients with malignant gliomas that had received two courses of chemotherapy more than 2 months apart were examined. Among these 42 patients, 31 were treated with 1-(4-amino-2-methyl-5-pyrimidynyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), and 11 were treated with platinum compounds such as cis-platinum (CDDP) or carboplatin (CBDCA), as the first-line chemotherapy. The response rate of the second chemotherapy in the 31 patients treated first with ACNU was significantly lower than that in the 11 patients treated with platinum compounds, regardless of the type of the second chemotherapy (P=0.0292 by Fisher's exact probability test). O(6)-methylguanine-DNA methyltransferase (MGMT) mRNA expression was measured twice by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) using Sybr-Green I in 16 of 42 patients. The relative quantitation value (RQV) of MGMT mRNA normalized to the level of 2-microglobulin decreased after chemotherapy in all 5 patients treated with platinum compound. U373MG and A172 human glioma cells were cultured for 5 days with 1 microM of CDDP or 4 microM of CBDCA. The RQV of MGMT in these cells treated with platinum compounds obviously decreased, and these cells were more sensitive to ACNU than the control cells based on colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Both the clinical findings and laboratory results suggest that platinum compounds may play a role in the down-regulation of MGMT mRNA expression and up-regulation of the sensitivity to ACNU. Platinum compounds may be strong candidates for use as first-line chemotherapeutic agents against malignant gliomas.
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PMID:Down-regulation of O6-methylguanine-DNA methyltransferase gene expression in gliomas by platinum compounds. 1621 Dec 96

Low-grade gliomas (LGG) are a group of uncommon neuroglial tumors of the central nervous system. They are characterized by a grade I or II according to the WHO classification. Grade I tumors are non-invasive and amenable to surgical resection with curative intent. Diffuse infiltrating LGG (WHO grade II) are tumors with a highly variable prognosis. Curative resection can only rarely be achieved and progression is characterized by transformation into a high-grade glioma (WHO grade III-IV). There are only limited evidence-based treatment recommendations for the management of progressive LGG because of a lack of data from prospective randomized trials. Most often radiotherapy is offered to patients with symptomatic and/or progressive disease. Three randomized trials have failed to demonstrate a survival improvement with either early versus delayed radiation or with a higher dose of radiation. The potential role of chemotherapy for the treatment of LGG has only been addressed in phase II trials. The PCV-chemotherapy regimen is associated with considerable toxicity that limits its applicability. The results with temozolomide (TMZ) chemotherapy have been more promising. Patients with chemosensitive LGG as predicted by heterozygotic loss of chromosomal arms Ip and 19q or methylation of the promoter of the MGMT-gene in the genome of the glioma cells respond to TMZ. Radiotherapy will be compared to chemotherapy asfirst line treatment for LGG in two phase III studies that are planned for by the brain tumor group of the European Organization for Research and Treatment of Cancer (BTG-EORTC) and Radiation Therapy Oncology Group (RTOG).
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PMID:The role of chemotherapy in the treatment of low-grade glioma. A review of the literature. 1625 51

Cerebral oligodendrogliomas represent more than 30% of glial tumors in adults. Mean age at diagnosis is 41 for grade A and 45(1/2) for grade B, epilepsy being the main revealing symptom (91.5% of A, 76% of B). Survival at 5, 10 and 15 years is respectively 75.5%, 51% and 22.4% for grade A (median: 136 months), and 45.2%, 31.3% and 0% for grade B (median: 52 months). It is influenced by age at diagnosis: median, before 40 years of age, is 12 years for A and 8(1/2) for B; between 40 and 60, is 12 years for A and 4(1/2) for B; over 60, is 4 years for A and 1(1/2) for B. In children, they represent less than 2.5% of cerebral tumors and include 23% grade A and 77% grade B (48.5% WHO grade II and 51.5% WHO grade III). Mean age at surgical removal is 9.5 +/- 5 years. One third are hemispheric, 2/3 are revealed by epilepsy. A complete surgical removal is performed in 60%. Mean survival is 13 years (154 +/- 20 months), with a mortality at 5 and 10 years of 60% +/- 9%, and a risk of recurrence of 54% +/- 9% at 5 years and 46.5% +/- 10.5% at 5 years. The main differential diagnosis of grade A oligo is dysembryoplastic neuroepithelial tumors (DNT). Inversely, thalamic locations, most often grade B, generally present with a motor deficit; complete removal can be achieved in only 15%. The only efficient treatment is chemotherapy, requiring search for chemosensitivity (1p19q deletion, expression of MGMT gene, analysis by MR-spectroscopy and TEP). Logically, surgical debulking should be as wide as possible, but with preservation of neurological and cognitive functions with the help of modern imaging progresses (fMRI, diffusion and perfusion MRI, tractography, PET) and operative techniques (navigation, cortical stimulation, and even opertaive MRI). Tumors presenting clinical and radiological progression should be removed. Operative mortality varies from 0 to 6%, transient morbidity from 20 to 25%, definit morbidity from 5 to 10%. Radiotherapy does not significantly modify survival whatever the delivered dose. The important point is the patient's radiosensitivity: survival is 148 months for radiosensitive patients versus 12 months for non responsive patients. Studies and development of pretherapeutic assays of tumoral radiosensitivity will be a fundamental research axis (PET, sample studies).
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PMID:Cerebral oligodendrogliomas in adults and children. Current data and perspectives. 1629 83

1. O6-methylguanine-DNA methyltransferase (MGMT) mRNA was measured in 50 malignant gliomas that had received 1-(4-amino-2-methyl-5-pyrimidynyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) after the resection of the tumor by real-time reverse transcription-polymerase chain reaction (RT-PCR) using TaqMan probe. 2. The mean absolute value of MGMTmRNA normalized to the level of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for 50 tumors was 1.29 x 10(4)+/- 1.28 x 10(4) copy/microg RNA (mean +/- SD). The amount of MGMTmRNA less than 6 x 10(3) copy/microg RNA was the most significant factor in predicting the initial effect of treatment with ACNU by multi-variant regression analysis (p = 0.0157). 3. These results suggest that quantitation of MGMTmRNA is the excellent method for predicting for the effect of ACNU in glioma therapy.
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PMID:Quantitation of O6-methylguanine-DNA methyltransferase gene messenger RNA in gliomas by means of real-time RT-PCR and clinical response to nitrosoureas. 1639 37

Several recent studies have further clarified the role of chemotherapy in newly diagnosed anaplastic glioma. For newly diagnosed glioblastoma, combined daily radiotherapy with daily temozolomide followed by six cycles of adjuvant temozolomide improves overall survival. This benefit is especially observed in patients with a methylated promotor of the MGMT gene which encodes an alkyltransferase; this observation however, needs confirmation. Although oligodendroglial tumours are sensitive to chemotherapy, classical adjuvant nitrosourea-based chemotherapy does not improve overall survival in newly diagnosed anaplastic oligodendroglioma, even in the subset of 1p/19q loss tumours. It may increase progression-free survival however, and further studies must show if combined modality treatment with daily chemotherapy during radiotherapy increases survival. Trials exploring the role of chemotherapy in low-grade glioma are ongoing. No standard chemotherapy is currently available for highly anaplastic glioma failing first-line temozolomide-based therapy.
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PMID:Recent developments in the use of chemotherapy in brain tumours. 1642 78

Early detection of tumor response to chemotherapy is of great importance for appropriate treatment of tumors. In this study, characteristics of two positron emission tomography (PET) tracers, [(18)F]2-fluoro-2-deoxy-D-glucose (FDG) and[(18)F]3'-fluoro-3'-deoxy-thymidine (FLT), in the early detection of tumor cell response as well as tolerance development to chemotherapy was compared using rat C6 glioma cells and 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosoureahydrochloride (ACNU). ACNU is an alkylating agent known to induce drug resistance through expression of O(6)-methylguanine-deoxyribonucleic acid methyl transferase (O(6)-MGMT). We established an ACNU-resistant C6 glioma cell line (C6/ACNU) and investigated the effect of ACNU on the uptake of FLT and FDG. In C6 cells, DNA synthesis presented as [(3)H]thymidine ([(3)H]Thd) incorporation into DNA was quickly suppressed by ACNU. In C6/ACNU cells, the suppression was recovered promptly, indicating that DNA alkylation occurs initially but highly expressed O(6)-MGMT repairs DNA, leading to the recovery of DNA synthesis. The patterns of FLT uptake in C6 and C6/ACNU were difficult to distinguish in the very early stage of the treatment, though it was reported that FLT uptake well correlated with proliferation in certain conditions. FDG uptake showed different patterns between the resistant and control cells, with significantly decreased uptake in C6 cells and unchanged uptake in C6/ACNU cells at 18-24 h after the treatment. Though difficult to be directly translated into clinical situation, the present study will provide a base to develop an appropriate protocol to assess tumor response to treatment by PET and to design effective treatment plans.
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PMID:Acquisition of resistance to antitumor alkylating agent ACNU: a possible target of positron emission tomography monitoring. 1645 56

Methylating drugs such as temozolomide (TMZ) are widely used in the treatment of brain tumours (malignant gliomas). The mechanism of TMZ-induced glioma cell death is unknown. Here, we show that malignant glioma cells undergo apoptosis following treatment with the methylating agents N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and TMZ. Cell death determined by colony formation and apoptosis following methylation is greatly stimulated by p53. Transfection experiments with O(6)-methylguanine-DNA methyltransferase (MGMT) and depletion of MGMT by O(6)-benzylguanine showed that, in gliomas, the apoptotic signal originates from O(6)-methylguanine (O(6)MeG) and that repair of O(6)MeG by MGMT prevents apoptosis. We further demonstrate that O(6)MeG-triggered apoptosis requires Fas/CD95/Apo-1 receptor activation in p53 non-mutated glioma cells, whereas in p53 mutated gliomas the same DNA lesion triggers the mitochondrial apoptotic pathway. This occurs less effectively via Bcl-2 degradation and caspase-9, -2, -7 and -3 activation. O(6)MeG-triggered apoptosis in gliomas is a late response (occurring >120 h after treatment) that requires extensive cell proliferation. Stimulation of cell cycle progression by the Pasteurella multocida toxin promoted apoptosis whereas serum starvation attenuated it. O(6)MeG-induced apoptosis in glioma cells was preceded by the formation of DNA double-strand breaks (DSBs), as measured by gammaH2AX formation. Glioma cells mutated in DNA-PK(cs), which is involved in non-homologous end-joining, were more sensitive to TMZ-induced apoptosis, supporting the involvement of DSBs as a downstream apoptosis triggering lesion. Overall, the data demonstrate that cell death induced by TMZ in gliomas is due to apoptosis and that determinants of sensitivity of gliomas to TMZ are MGMT, p53, proliferation rate and DSB repair.
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PMID:Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. 1681 6


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