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

---

Query: UMLS:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Randomized trials have demonstrated Gliadel improves survival for appropriately selected patients with newly diagnosed malignant glioma. As only limited information is available to guide the management of patients who have Gliadel controlled-release BCNU wafers implanted in the cranial resection cavity prior to radiotherapy (RT), this retrospective review was conducted to describe clinical course, toxicity, and pathologic findings after this therapy for newly diagnosed malignant glioma. Forty-six consecutive patients receiving Gliadel (3.8% BCNU impregnated wafers) followed by radiotherapy for newly diagnosed malignant glioma at Johns Hopkins Hospital from 1990 to August 1999 were identified, although one was lost to follow up and is excluded. Patients were evaluated for postoperative infection, pathology at reoperation, and survival. Twenty-eight patients received radiotherapy at Johns Hopkins and these patients are also evaluable for toxicity experienced during and one month after completion of RT. The median age of all patients is 57 years. Eighty-nine percent had glioblastoma, and median follow-up of surviving glioblastoma patients is 16.8 (12-20) months. Postoperative infection or need for reoperation within 30 days was uncommon after Gliadel placement. Full-dose radiotherapy was tolerable after Gliadel implantation. Five patients (19%) developed neurologic symptoms during radiotherapy responding to increased steroids and/or anticonvulsants, whereas an additional 8 of 27 (30%) developed neurologic symptoms during dexamethasone taper that responded to increases in dexamethasone dose. At one month after RT, 58% of patients were still on dexamethasone despite attempted taper. Fifteen of 45 patients, 33% underwent reoperation or biopsy for a new local contrast-enhancing lesion. In five of 15 (33%) the reoperation revealed necrosis or treatment effect without active tumor. Two of five patients with treatment/effect necrosis has a third surgery 2.9 and 3.2 months after the initial reoperation, and treatment effect/necrosis without tumor was demonstrated in both cases. The Kaplan-Meier median survival for all the glioblastoma patients is 12.8 (95% CI 9.6, 15.9) months. For glioblastoma patients under 55 years old, median survival is 15.9 (95% CI 13.5, too few events) months whereas for older patients it is 9.6 (7.7, 14.4) months. We conclude that Gliadel followed by full-dose standard radiotherapy is acutely well tolerated, although, close supervision should be emphasized during dexamethasone taper. Median survival in excess of one year suggests that there are not complications that result in overall premature death. The finding of necrosis/treatment effect was noted in five of 45 (11%) of all patients and five of 15 (33%) of those undergoing reoperation. Therefore, the possibility of necrosis/treatment effect should be considered for each patient with radiographic findings suspicious for local recurrence.
...
PMID:Clinical course and pathologic findings after Gliadel and radiotherapy for newly diagnosed malignant glioma: implications for patient management. 1506 76

We conducted a study to determine the dose-limiting toxicity of an extended dosing schedule of temozolomide (TMZ) when used with a fixed dose of BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea (carmustine), taking advantage of TMZ's ability to deplete O6-alkylguanine-DNA-alkyltransferase and the synergistic activity of these two agents. Patients with malignant gliomas who had undergone radiation therapy were eligible. Patients were treated with TMZ for 28 days, followed by a 28-day rest (1 cycle). The TMZ was started at 50 mg/m2 and increased in 10-mg/m2 increments; a fixed dose of BCNU (150 mg/m2) was given within 72 h of starting TMZ. A standard phase 1 dose-escalation scheme was used with 3 patients per cohort. Fourteen glioblastoma patients and 10 anaplastic astrocytoma patients were treated. The dose-limiting toxicity was myelosuppression at 90 mg/m2 of TMZ. The total number of cycles given was 73 (median number was 2). Six patients (25%) required a dose reduction in BCNU, and six were removed from study for hematologic toxicity after cycle 1; three patients overlapped. The median time to progression and overall survival were, respectively, 82 and 132 weeks for anaplastic astrocytomas and 14 and 69 weeks for glioblastomas. We conclude that the combination of BCNU and the extended dosing schedule of TMZ is feasible and that the maximal tolerated dose of a 28-day course of TMZ is 80 mg/m2 when combined with a fixed dose of BCNU at 150 mg/m2. This is the recommended dose for phase 2, but myelosuppression after cycle 1 suggests that long-term treatment may be difficult.
...
PMID:Phase 1 study of 28-day, low-dose temozolomide and BCNU in the treatment of malignant gliomas after radiation therapy. 1527 17

Oligodendroglial differentiation in gliomas is associated with enhanced sensitivity to chemotherapy. Antiapoptotic proteins, Bcl-xL and Bcl-2, are over-expressed in early passage cell lines derived from glioblastomas. Down-regulation of Bcl-xL and Bcl-2 with DNA antisense oligonucleotides promotes cell death in glioblastoma cells. Changes of expression of Bcl-xL and Bcl-2 after chemotherapy treatment have not been studied in glioma subtypes. The current experiments correlate decreased expression of both Bcl-xL and Bcl-2 after BCNU chemotherapy and cell death in two oligodendroglioma-derived cell lines. Expression of Bcl-2 family member proteins Bcl-xL, Bcl-2, and Bax were assessed in glioma cells both before and after chemotherapy treatment. Cell survival was assessed with a crystal violet bioassay. Levels of expression of Bcl-2 and Bcl-xL were elevated in two early passage oligodendroglioma-derived cell lines compared with a non-neoplastic glial cell line. BCNU chemotherapy markedly down-regulated expression of Bcl-xL and Bcl-2 proteins in both oligodendroglioma-derived cell lines. Changes in expression of Bcl-xL and Bcl-2 were associated with the increased sensitivity to chemotherapy. There were no changes noted in expression of Bax after BCNU treatment. Modulation of expression of the anti-apoptotic proteins, Bcl-xL and Bcl-2, in the two oligodendroglioma-derived cell lines was associated with increased sensitivity to BCNU chemotherapy. Down-regulation of Bcl-xL and Bcl-2 resulted in reversal of the ratio of Bax/Bcl-xL and Bax/Bcl-2 and enhanced cell death after treatment with BCNU. Mechanisms that control expression of the anti-apoptotic proteins Bcl-xL and/or Bcl-2 may be effective targets in treatment strategies in patients with malignant gliomas.
...
PMID:BCNU down-regulates anti-apoptotic proteins bcl-xL and Bcl-2 in association with cell death in oligodendroglioma-derived cells. 1533 26

The purpose of this study was to evaluate the potential selection bias using stereotactic eligibility as a criteria for participation in studies of glioblastoma multiforme. Radiation Therapy Oncology Group (RTOG) 90-06 comparing 60 Gy in 30 fractions with BCNU and 72 Gy in 60 fractions with BCNU was analyzed based on eligibility criteria used to enter patients on RTOG 93-05 using a stereotactic boost for patients with glioblastoma. Five hundred nine patients with histopathologically confirmed glioblastoma multiforme were analyzed; of these, 137 met criteria for 93-05 and 372 did not. Recursive partitioning analysis (RPA) was used to evaluate for differences. The RPA distribution in stereotactic radiosurgery (SRS)-eligible and -ineligible patients was similar. The median survival for RPA class 3 SRS-eligible patients was 1.4 years and -ineligible patients 1.4 years. For RPA class 4, the median survival was 1.0 years for eligible patients and 0.9 years for ineligible patients (P = 0.0421). For class 5 patients, the median survival was 8.3 months versus 7.2 months (P = 0.09). RPA class 6 patients had a median survival of 1.7 months versus 2.7 months for ineligible patients (P = 0.199). By analyzing previously randomized patients in a study not using a stereotactic boost, there does not appear to be a survival benefit for those patients who fit the criteria for consideration of a stereotactic boost in patients with glioblastoma multiforme.
...
PMID:Does stereotactic eligibility for the treatment of glioblastoma cause selection bias in randomized studies? 1559 23

We compared the cytotoxicity of the bioreductive antitumor agents mitomycin C (MMC) and streptonigrin (SN) with or without the DT-diaphorase (DTD) inducer dimethyl fumarate (DMF) in four human glioblastoma cell lines with the conventional chemotherapeutic agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We also examined four other types of cancer cells to compare with glioblastoma cells. Cytotoxicity was measured with the sulforhodamine B (SRB) assay and was represented by 50% inhibition concentration (IC50). Enzymatic activities of DTD, cytochrome b5 reductase and glutathione-S-transferase (GST) in cells were measured spectrophotometrically. IC50 for BCNU was in a range of 28-300 microM in the glioblastoma cell lines. Glioblastoma cells were more sensitive to MMC or SN than to BCNU. Pretreatment with DMF significantly increased cytotoxicity of MMC and SN in glioblastoma cell lines and the NCI-H1299 lung cancer cell line, but had no effect on BCNU cytotoxicity. DMF significantly increased DTD and cytochrome b5 reductase activity, and decreased GST in three of four glioblastoma cell lines. Addition of the DTD inhibitor, dicumarol, significantly inhibited cytotoxicity of MMC and SN, and reversed the increased cytotoxicity seen when DMF was combined with either MMC or SN in all glioblastoma cell lines. Combining inducers of DTD and cytochrome b5 reductase with bioreductive agents may be a potential therapeutic strategy for glioblastoma.
...
PMID:Enhanced cytotoxicity of bioreductive antitumor agents with dimethyl fumarate in human glioblastoma cells. 1565 14

3-halo-4,5-dihydroisoxazoles are attractive warheads for the selective inhibition of nucleophilic active sites in biological systems. A series of 3-bromo-4,5-dihydroisoxazole compounds were prepared and tested for their ability to irreversibly inhibit human transglutaminase 2 (TG2), an enzyme that plays an important role in the pathogenesis of diverse disorders including Celiac Sprue and certain types of cancers. Several compounds showed high specificity for human TG2 (k(inh)/K(I) > 2000 min(-1)M(-1)) but essentially no reactivity (k < 1 min(-1)M(-1)) toward physiological thiols such as glutathione. The pharmacokinetic and pharmacodynamic properties of a prototype dihydroisoxazole inhibitor, 1b, were evaluated; in mice the compound showed good oral bioavailability, short serum half-life and efficient TG2 inhibition in small intestinal tissue, and low toxicity. It also showed excellent synergism with N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU, carmustine) against refractory glioblastoma tumors in mice. A fluorescent dihydroisoxazole inhibitor 5 facilitated microscopic visualization of TG2 endocytosis from the extracellular surface of HCT-116 cells. Together, these findings demonstrate the promise of dihydroisoxazole compounds as probes for the biology of TG2 and its role in human disease.
...
PMID:Chemistry and biology of dihydroisoxazole derivatives: selective inhibitors of human transglutaminase 2. 1585 Sep 75

BCNU (1,3-bis[2-chloroethyl]-1-nitrosourea) is the mainstay in glioblastoma multiform chemotherapy with only minimal effects. BCNU may kill tumor cells via carbamoylating cytotoxicity, which irreversibly inhibits glutathione reductase with resultant accumulation of oxidized form of glutathione causing oxidative stress. S-nitrosoglutathione (GSNO) is a product of glutathione and nitric oxide interaction. We report that GSNO formation may underlie carbamoylating chemoresistance mediated by activation of inducible nitric oxide synthase. Transactivation of hypoxia-inducible factor-1 (HIF-1)-responsive genes reduces oxidative stress caused by glutathione depletion. We also noted that preconditioning of C6 glioma cells to induce HIF-1 and its downstream genes confers chemoresistance against carbamoylating cytotoxicity of BCNU.
...
PMID:S-nitrosoglutathione and hypoxia-inducible factor-1 confer chemoresistance against carbamoylating cytotoxicity of BCNU in rat C6 glioma cells. 1596 67

Tissue transglutaminase 2 belongs to a family of transglutaminase proteins that confers mechanical resistance from proteolysis and stabilizes proteins. Transglutaminase 2 promotes transamidation between glutamine and lysine residues with the formation of covalent linkages between proteins. Transglutaminase 2 also interacts and forms complexes with proteins important in extracellular matrix organization and cellular adhesion. We have identified the novel finding that treatment of glioblastoma cells with transglutaminase 2 inhibitors promotes cell death and enhances sensitivity to chemotherapy. Treatment with either the competitive transglutaminase 2 inhibitor, monodansylcadaverine, or with highly specific small-molecule transglutaminase 2 inhibitors, KCA075 or KCC009, results in induction of apoptosis in glioblastoma cells. Treatment with these transglutaminase 2 inhibitors resulted in markedly decreased levels of the prosurvival protein, phosphorylated Akt, and its downstream targets. These changes promote a proapoptotic profile with altered levels of multiple intracellular proteins that determine cell survival. These changes include decreased levels of the antiapoptotic proteins, survivin, phosphorylated Bad, and phosphorylated glycogen synthetase kinase 3beta (GSK-3beta), and increased levels of the proapoptotic BH3-only protein, Bim. In vivo studies with s.c. murine DBT glioblastoma tumors treated with transglutaminase 2 inhibitors combined with the chemotherapeutic agent, N-N'-bis (2-chloroethyl)-N-nitrosourea (BCNU), decreased tumor size based on weight by 50% compared with those treated with BCNU alone. Groups treated with transglutaminase 2 inhibitors showed an increased incidence of apoptosis determined with deoxynucleotidyl transferase-mediated biotin nick-end labeling staining. These studies identify inhibition of transglutaminase 2 as a potential target to enhance cell death and chemosensitivity in glioblastomas.
...
PMID:Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas. 1617 20

Glioblastomas are among the most difficult neoplasms to treat with continued poor prognosis for long-term survival. Glioblastomas have developed effective mechanisms to resist chemotherapy including levels anti-apoptotic proteins, Bcl-xL and Bcl-2. Chemotherapy agents that promote down-regulation of Bcl-xL and Bcl-2 may enhance sensitivity to chemotherapy in glioblastomas. The ability of the synthetic retinoid N-(4-hydroxyphenyl) retinamide to modulate these anti-apoptotic proteins and to enhance apoptosis and chemotherapy was examined in glioblastoma cells. Expression of Bcl-2 family member proteins Bcl-xL and Bcl-2 were assessed in glioblastomas from three cell lines including U87, U251, and U138. Cells were treated with either retinamide alone or in combination with the chemotherapy agent, BCNU. The incidence of apoptosis was determined with flow cytometry analysis (FACS). Based on Western blots the levels of Bcl-2 and Bcl-xL were decreased in glioblastoma cells after treatment with retinamide. Retinamide treatment resulted in increased ratios of deamidated verses transamidated levels of Bcl-xL in U87 cells. BCNU chemotherapy combined with retinamide markedly down-regulated levels of both Bcl-xL and Bcl-2 proteins in glioblastoma and enhanced the incidence of apoptosis in U87 cells. These studies demonstrate that modulation of levels of the anti-apoptotic proteins, Bcl-xL and Bcl-2, may enhance the sensitivity of glioblastoma toward chemotherapy.
...
PMID:Retinamide-induced apoptosis in glioblastomas is associated with down-regulation of Bcl-xL and Bcl-2 proteins. 1618 19

Preclinical studies support the concept that inhibition of protein kinase C (PKC) by tamoxifen (TAM) should provide both antineoplastic effects and radiosensitization. High-dose TAM (80 mg/m2 p.o. daily in divided doses) was given with and after conventional radiotherapy (XRT) to inhibit PKC-mediated signaling, which is known to be enhanced in glioblastoma (GBM). Seventy-seven patients were accrued between December 2000 and December 2001; two were ineligible and not included in the efficacy results. Pretreatment characteristics of the patients included the following: 52% were less than 60 years of age, 39% had a Zubrod score of 0, 70% had minor or no neurological symptoms, and 65% were Radiation Therapy Oncology Group-recursive partition analysis (RPA) class III and IV. Eighty-six percent of patients achieved acceptable dosing of TAM. Notable toxicity included late radiation grade 3 in two patients and thromboembolic events in 16 patients (two grade 2, 10 grade 3, three grade 4, and one grade 5), for an incidence of 20.8% (which is lower than expected, based on the literature for deep vein thrombophlebitis in GBM patients not receiving TAM). Median survival time (MST) was 9.7 months as compared (by three different statistical methodologies) to the historical GBM control database of 1457 RPA class III, IV, and V drug/XRT-treated patients. After controlling for RPA class IV, the MST was 11.3 months, which compares to the historical RPA control of 11.3 months (P = 0.37). The results obtained do not exhibit a substantial advance over those of previous studies with various XRT/drug doublets, including BCNU. However, as TAM does not have significant overlapping toxicities with most other drugs, its testing in a combined modality approach with other medications may be justified in future clinical trials. Historically, the incidence of thromboembolic events in GBM patients is approximately 30%. The lower-than-expected incidence seen here has also been observed in other high-dose TAM GBM studies. We speculate that TAM inhibited the PKC-mediated phosphorylation of coagulation factors.
...
PMID:Phase 2 trial of radiation plus high-dose tamoxifen for glioblastoma multiforme: RTOG protocol BR-0021. 1644 47


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---