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)

Treatment of malignant glioma requires a multidisciplinary team. Treatment includes surgery, radiotherapy, and chemotherapy. Recently developed agents have demonstrated activity against recurrent malignant glioma and efficacy if given concurrently with radiotherapy in the upfront setting. Oligodendroglioma with 1p/19q deletions has been recognized as a distinct pathologic entity with particular sensitivity to radiotherapy and chemotherapy. Randomized trials have shown that early neoadjuvant or adjuvant administration of procarbazine, lomustine, and vincristine chemotherapy prolongs disease-free survival; however, it has no impact on overall survival. Temozolomide, a novel alkylating agent, has shown modest activity against recurrent glioma. In combination with radiotherapy in newly diagnosed patients with glioblastoma, temozolomide significantly prolongs survival. Molecular studies have demonstrated that the benefit is mainly observed in patients whose tumors have a methylated methylguanine methyltransferase gene promoter and are thus unable to repair some of the chemotherapy-induced DNA damage. For lower-grade glioma, the use of chemotherapy remains limited to recurrent disease, and first-line administration is the subject of ongoing clinical trials. Irinotecan and agents like gefitinib, erlotinib, and imatinib targeting the epidermal growth factor receptor and platelet-derived growth factor receptor have shown some promise in recurrent malignant glioma. This review summarizes recent developments, focusing on the clinical management of patients in daily neuro-oncology practice.
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PMID:Changing paradigms--an update on the multidisciplinary management of malignant glioma. 1647 37

Temozolomide (TMZ) is an alkylating agent earlier approved for recurrent anaplastic astrocytoma and approved for the treatment of newly diagnosed glioblastoma in the USA and Europe in 2005. TMZ shows good blood-brain barrier penetration and exhibits a favorable side effect profile. Its key mode of action appears to be methylation at N(7) and O(6)-positions of guanine. The level of expression and activity of the DNA repair enzyme O(6)-methylguanine DNA methyltransferase is thought to be a major predictor of response to TMZ. The demonstration of prolonged survival when TMZ was added to radiotherapy in the European Organisation for Research and Treatment of Cancer 26981/22981/NCIC CE.3 trial has been a breakthrough in the treatment of newly diagnosed glioblastoma. The early preliminary evidence for activity in recurrent malignant gliomas further resulted in a broad evaluation of TMZ for other tumors in neuro-oncology, mainly low-grade gliomas, brain metastases and primary cerebral lymphomas.
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PMID:Temozolomide: a milestone in the pharmacotherapy of brain tumors. 1655 52

Malignant gliomas, among which glioblastomas constitute the largest group, are characterized by a dramatically diffuse infiltration into the brain parenchyma with, as a consequence, the fact that no patient with glioblastoma multiforme (GBM) has been cured to date. Migrating GBM cells are resistant to apoptosis (Type I programmed cell death), and thus to radiotherapy and conventional chemotherapy, because of the constitutive activation of several intracellular signaling pathways, of which the most important identified to date are the pathways controlled by phosphatidylinositol 3-kinase, Akt, and the mammalian target of rapamycin (mTOR). Migrating GBM cells seem to be less prone to resist autophagy (Type II programmed cell death), and disruption of the pathway controlled by mTOR induces marked autophagic processes in GBM cells. Temozolomide is the most efficacious cytotoxic drug employed today to combat glioblastoma, and this drug exerts its cytotoxic activity through proautophagic processes. Thus, autophagy represents a kind of Trojan horse that can be used to bypass, at least partly, the dramatic resistance of glioblastoma to radiotherapy and proapoptotic-related chemotherapy.
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PMID:Autophagy, the Trojan horse to combat glioblastomas. 1670 38

Glioblastoma is a highly angiogenic tumor with a dismal prognosis. Temozolomide (TMZ), a methylating agent is one of the most effective chemotherapeutic agents against glioblastoma. To overcome the problem that most of these tumors become resistant to chemotherapeutic regimens within a year, we investigated the antitumor efficacy of metronomic administration of low-dose TMZ in in vitro cell proliferation/cytotoxicity assay and in vivo rat and nude mouse orthotopic glioma model. By in vitro assay, we elucidated that C6/LacZ rat glioma cells were more resistant to metronomic treatment of TMZ than U-87MG human glioblastoma cells and bEnd.3 mouse brain endothelial cells. Compared with the conventional chemotherapeutic regimen of TMZ, we found that frequent administration of TMZ at a low dose (metronomic treatment) markedly inhibited angiogenesis as well as tumor growth in a TMZ-resistant C6/LacZ rat glioma model. In addition, metronomic treatment of TMZ significantly augmented apoptosis of tumor cells in this model. For the TMZ-sensitive U-87MG cells, even with a very low dose of TMZ, which is not effective to reduce tumor mass, the metronomic treatment of TMZ reduced the microvessel density, i.e. angiogenesis, in a nude mouse orthotopic model. In conclusion, for both models, the metronomic treatment of TMZ decreased angiogenesis. Especially, in TMZ-resistant glioma cells, this regimen increased apoptosis of tumor cells and decreased tumor growth. The metronomic treatment of TMZ in orthotopic glioma models demonstrated a successful antiangiogenic effect which can overcome the chemoresistance in conventional TMZ chemotherapy.
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PMID:Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas. 1678 20

Previously we defined a pathway of transforming growth factor beta (TGF-beta) and stromal cell-derived factor-1/CXC chemokine ligand 12 (SDF-1alpha/CXCL12) dependent migration of adult haematopoietic stem and progenitor cells (HPC) towards glioma cells in vitro and their homing to experimental gliomas in vivo. Hypoxia is a critical aspect of the microenvironment of gliomas and irradiation is an essential part of the standard therapy. To evaluate the therapeutic potential of HPC as vectors for a cell-based therapy of gliomas, we investigated the impact of hypoxia and irradiation on the attraction of HPC by glioma cells. Temozolomide (TMZ) treatment and hyperthermia served as controls. Supernatants of irradiated or hypoxic LNT-229 glioma cells promote HPC migration in vitro. Reporter assays reveal that the CXCL12 promoter activity is enhanced in LNT-229 cells at 24 h after irradiation at 8 Gy or after exposure to 1% oxygen for 12 h. The irradiation- and hypoxia-induced release of CXCL12 depends on hypoxia inducible factor-1 alpha (HIF-1alpha), but not on p53. Induction of transcriptional activity of HIF-1alpha by hypoxia or irradiation requires an intact TGF-beta signalling cascade. This delineates a novel stress signalling cascade in glioma cells involving TGF-beta, HIF-1alpha and CXCL12. Stress stimuli can be irradiation, hypoxia or TMZ, but not hyperthermia. Cerebral irradiation of nude mice at 21 days after intracerebral implantation of LNT-229 glioma induces tumour satellite formation and enhances the glioma tropism of HPC to the tumour bulk and even to these satellites in vivo. These data suggest that the use of HPC as cellular vectors in the treatment of glioblastoma may well be combined with irradiation or other anti-angiogenic therapies that induce tumour hypoxia.
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PMID:Irradiation and hypoxia promote homing of haematopoietic progenitor cells towards gliomas by TGF-beta-dependent HIF-1alpha-mediated induction of CXCL12. 1683 50

Temozolomide (Temodal, Temodar), an imidazol derivative, is a second-generation alkylating agent. The orally available prodrug with the capacity of crossing the blood-brain barrier received accelerated US FDA approval in 1999. Three pivotal Phase II trials showed modest activity in the treatment of recurrent anaplastic astrocytoma glioblastoma. In 2005, the FDA and the European Agency for the Evaluation of Medicinal Products approved temozolomide for use in newly diagnosed glioblastoma, in conjunction with radiotherapy, based on an European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada Phase III trial. The adverse events associated with temozolomide are mild-to-moderate and generally predictable; the most serious are noncumulative and reversible myelosuppression and, in particular, thrombocytopenia, which occurs in less than 5% of patients. Continuous temozolomide administration is associated with profound CD4-selective lymphocytopenia. Molecular studies have suggested that the benefit of temozolomide chemotherapy is restricted to patients whose tumors have a methylated methylguanine methyltransferase gene promotor and are thus unable to repair some of the chemotherapy-induced DNA damage. Temozolomide is under investigation for other disease entities, in particular lower-grade glioma, brain metastases and melanoma.
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PMID:Temozolomide: a milestone in neuro-oncology and beyond? 1692 85

Glioblastoma multiforme is the most common primary brain tumor in adults. Until recently, the standard of care consisted of maximal surgical resection followed by external beam radiotherapy. The role of adjuvant chemotherapy for newly diagnosed glioblastoma has been controversial; most of the numerous randomized phase III trials conducted over the past 40 years have failed to show a statistically significant and clinically meaningful survival advantage for patients randomized to the chemotherapy arm. Consequently, the choices of chemotherapeutics for patients with glioblastoma have been limited, and cytotoxic treatment regimens have usually included a nitrosourea. Temozolomide, a relatively new orally administered methylating agent, has demonstrable activity in glioma. A recent trial conducted under the auspices of the European Organization for the Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) has defined a role for temozolomide in the initial management of glioblastoma. A companion correlative tumor-biology study has identified epigenetic silencing of the promoter of the gene that encodes MGMT (O6-methylguanine-DNA methyltransferase) in tumor specimens as a strong and independent prognostic factor for survival among patients with a newly diagnosed glioblastoma, as well as a predictor of survival benefit from chemoradiotherapy with temozolomide. This review briefly summarizes the development of temozolomide as a therapy for patients with malignant brain tumors, emphasizing recent trials that have established a new standard of care for patients with glioblastoma and speculating on how these advances might influence future therapeutic investigations for malignant primary brain tumors.
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PMID:Drug Insight: temozolomide as a treatment for malignant glioma--impact of a recent trial. 1693 4

Data from a prospective trial large enough to provide a reliable analysis of outcome and prognostic factors in elderly patients with glioblastoma (GBM) are not yet available in the literature. Extensive tumor removal appears to offer patients the best possible chance of a speedy neurological recovery. Adequate radiotherapy (RT) should always be given to elderly patients if they have undergone gross total debulking and have maintained a good performance status. It is, however important to bear in mind that the risk of long-term cognitive impairment may be higher in patients on high-dose RT and that a short course of accelerated RT can achieve the same survival. Rather than being ruled out on principle, chemotherapy should be considered on the basis of an accurate assessment of the factors that might compromise the individual patient's tolerance to drugs administered. Temozolomide appears to be the best available chemotherapy in this population of patients.
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PMID:Glioblastoma in the elderly: current and future trends. 1702 78

Carmustine wafers (Gliadel) and temozolomide (Temodal) were recently approved for initial management of glioblastoma. Gliadel) is a polymer wafer containing carmustine. These wafers are designed to be placed in the surgical cavity after glioblastoma resection to deliver local chemotherapy. This treatment is intended for tumors for which gross total resection is possible. Temozolomide is administered concomitantly with radiotherapy for six weeks followed by six cycles of adjuvant temozolomide (EORTC 26981, also known as "Stupp's protocol"). Temozolomide administered according to this protocol produced a median survival benefit of 2 months in glioblastomas, and carmustine a similar benefit in high-grade gliomas. The two-year survival rate was 26.5% with radiotherapy plus temozolomide compared with 10.4% with radiotherapy alone. In patients with complete resection, two-year survival reached 38%. These two new treatments are essentially intended for patients younger than 70 years and with a Karnofsky index>70. Ongoing studies are evaluating the possible value of combining these two treatments.
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PMID:[What type of adjuvant chemotherapy should be proposed for the initial treatment of glioblastoma?]. 1735 Jul 91

To evaluate if timing of chemotherapy with Temozolomide (TMZ) was able to modify the outcome of glioblastoma (GBM), we analyzed two comparable series of supratentorial GBM patients, treated with surgery and radiotherapy, in which the administration of TMZ has been performed in the first group at first relapse and in the second group in newly diagnosed cases. The end-points were the median survival, the time tumor progression (TTP) and also the Karnofsky (KPS) scale and the Mini Mental State Examination (MMSE) scale at follow-up. From December 1999 to December 2001 30 patients with recurrent GBM received TMZ until progression. From January 2002 to January 2004 38 newly diagnosed patients received a first cycle of TMZ immediately after surgery, and additional cycles after completing radiotherapy until recurrence. In order to obtain a greater drug exposure we adopted a once-daily 10 days schedule of TMZ every 28 days as follows: 150 mg/m(2)/day (day 1-5) and 75 mg/m(2)/day (day 6-10). The first group had a median overall survival of 14 months and a median TTP of 6. The second group had a median survival of 16 months and a median TTP of 10. The difference of TTP was statistically significant (P < 0.001), while the overall survival was not. The values of KPS and MMSE at 12 months demonstrated a better quality of life in the second group (P < 0.01). Our regimen permitted to cover the therapeutic "window" between surgery and the beginning of radiotherapy in newly diagnosed cases and is well tolerated by the patients with limited side effects. We will propose as alternative option when the concomitant radio-chemotherapic protocol is not feasible.
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PMID:Temozolomide in glioblastoma: results of administration at first relapse and in newly diagnosed cases. Is still proposable an alternative schedule to concomitant protocol? 1736 34


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