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)

Despite aggressive treatment, the high-grade malignant glioma (specifically, anaplastic astrocytoma and glioblastoma multiforme) have a poor prognosis with current methods. Relapse is nearly universal, responses in recurrent disease are not enduring, and quality of life because of tumor growth is poor. New treatment strategies that address symptom control and quality of life as well as progression-free and overall survival are urgently needed. Temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ), a novel, oral, antineoplastic agent, has shown efficacy against high-grade glioma with a favorable safety profile, while maintaining or improving quality of life. In a pivotal randomized, international phase II trial comparing temozolomide (n = 112) with procarbazine (n = 113) in patients with glioblastoma multiforme, temozolomide significantly improved median and 6-month progression-free survival and 6-month overall survival. Additionally, patients receiving temozolomide had superior responses in all seven quality-of-life domains tested, which included the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire functions and brain-cancer-specific symptoms. A large, multicenter, single-arm trial (N = 162) showed an impressive response rate for patients with relapsed anaplastic astrocytoma receiving temozolomide, and patients maintained or improved their quality of life compared with baseline values. For patients with recurrent malignant glioma, temozolomide provides a therapeutic option with a predictable safety profile, clinical efficacy, and convenient dosing that can provide important quality-of-life benefits.
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PMID:Temozolomide for recurrent high-grade glioma. 1155 Jan 33

Temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) has several characteristics that make it appealing for combination therapies: broad-spectrum antitumor activity, the ability to cross the blood-brain barrier, a good safety profile with nonoverlapping toxicities, an oral formulation, and the ability to overcome resistance to nitrosoureas. Preclinical and phase I trials have shown the additive or synergistic activity of temozolomide combined with carmustine against solid tumors, including malignant glioma, and the sequence-dependent effects of the combination. Toxicity is lower and the maximum tolerated dose is higher when carmustine is given before temozolomide. Studies also have examined the combination of temozolomide with the topoisomerase I inhibitor irinotecan (CPT-11), an alkaloid derivative of camptothecin that has shown activity against malignant glioma. Temozolomide followed by CPT-11 was more effective than either agent alone. A major issue facing investigators now is determining which of the several schedules of temozolomide and CPT-11 are optimal. Completed and ongoing studies of temozolomide in combination with carmustine, including polifeprosan carmustine implant (Gliadel wafers; Aventis Pharmaceuticals, Parsippany, NJ), and CPT-11 are described.
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PMID:Temozolomide in combination with other cytotoxic agents. 1155 Jan 36

Although the initial indications of temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) therapy are for refractory central nervous system malignancies (anaplastic astrocytoma in the United States and Europe, glioblastoma multiforme in Europe), a number of clinical trials are planned or ongoing to evaluate the efficacy and safety of temozolomide in newly diagnosed glioma, oligodendroglioma, pediatric glioma, brain metastases, metastatic melanoma, and other systemic tumors. Also under investigation are modifications to the temozolomide dosing schedule, other routes of administration, and treatment regimens that include temozolomide in combination with other chemotherapeutic and biologic agents. Temozolomide has the potential to be a useful agent in the treatment of a variety of cancers.
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PMID:Future directions for temozolomide therapy. 1155 Jan 38

Gliomas are the most common primary intracerebral tumours and over 60% of these are malignant. Standard treatment in the UK for patients with a good performance status consists of surgery and postoperative radiotherapy, however, recurrence is almost inevitable. Treatment of recurrent malignant gliomas (MG) is limited to further surgery, chemotherapy and novel biological therapies. The response rate to standard chemotherapy protocols for recurrent MG is less than 30%. Temozolomide (Temodar-US, Temodal-Rest of World) is an oral alkylating agent with a similar chemical structure to dacarbazine, and has recently been licensed in the UK for second line treatment of recurrent MG. Several phase II studies and one randomised trial suggest that Temozolomide improves time to progression and quality of life but not overall survival. The drug is well tolerated with dose limiting myelosuppression and thrombocytopenia occurring in less than 10% of patients at current dosage schedules. A randomised trial comparing Temozolomide with best first line adjuvant chemotherapy (PCV) is about to start recruiting patients. Further clinical studies investigating its role in neoadjuvant treatment or in combination with radiotherapy or other chemotherapeutic approaches are ongoing.
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PMID:The use of temozolomide in recurrent malignant gliomas. 1229 19

Patients with malignant glioma continue to have a dismal outcome. Those with glioblastoma multiforme, the most common type of malignant glioma, have a median survival of 40 to 60 weeks following diagnosis and only 16 to 24 weeks after recurrence. While standard therapy is surgery and external-beam radiotherapy, data indicate that chemotherapy improves the clinical outcome of some patients. Irinotecan (CPT-11, Camptosar) possesses significant activity against malignant glioma, and potentiation of this activity with combination partners, including the alkylator 1,2-bis(2-chloroethyl)-1-nitrosourea (carmustine, BCNU), is being evaluated in an ongoing phase II study. Also, the combination of irinotecan plus temozolomide (Temodar) has produced synergism in preclinical studies as well as encouraging responses in ongoing clinical trials. Other investigative directions include studies of irinotecan plus temozolomide and O6-benzylguanine (O6-BG) to assess the ability of O6-BG to maximize the therapeutic benefits of irinotecan combined with temozolomide.
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PMID:Irinotecan: promising activity in the treatment of malignant glioma. 1280 Jun

The incidence of primary brain tumors has rapidly increased in recent years. The current standard of care for patients with high-grade malignant glioma is resection followed by radiotherapy. However, the use of adjuvant chemotherapy and the standard of care at first relapse are still under debate for patients with glioblastoma multiforme and anaplastic astrocytoma. Meta-analyses have suggested that adjuvant chemotherapy, specifically with nitrosourea-based regimens, is associated with improved survival. However, no randomized, controlled trial has shown a clear advantage for adjuvant chemotherapy in these patients. Cumulative toxicity associated with both radiotherapy and chemotherapy, as well as resistance to nitrosourea-based regimens related to exposure in the adjuvant setting, prevent the use of radiotherapy and nitrosourea-based regimens at first relapse. The combination of procarbazine, carmustine, and vincristine (PCV) has shown activity at first relapse in patients who have not received adjuvant chemotherapy. Temozolomide (Temodar [US], Temodal [international]; Schering-Plough Corporation, Kenilworth, NJ) has shown activity at both first and second relapse in patients who have received prior nitrosourea-based regimens. The better safety profile of temozolomide suggests that it may be preferred to PCV for treatment of patients with recurrent high-grade malignant glioma. Additional randomized, controlled trials are needed to fully define the best option for first-line chemotherapy in both the adjuvant and recurrent settings in patients with high-grade malignant glioma.
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PMID:State-of-the-art treatment of high-grade brain tumors. 1476 77

The current standard of care for patients with high-grade glioma is resection followed by radiotherapy. Adjuvant chemotherapy is not widely accepted because of the low sensitivity of gliomas to traditional antineoplastic agents, the poor penetration of most drugs across the blood-brain barrier, and the significant systemic toxicity associated with current agents. However, nitrosoureas and, subsequently, temozolomide (Temodar [US], Temodal [international]; Schering-Plough Corporation, Kenilworth, NJ), a novel alkylating agent, cross the blood-brain barrier and have activity against gliomas. Nitrosoureas have been studied in phase III trials in the adjuvant setting. In individual trials, chemotherapy did not increase median survival but did increase the proportion of patients surviving >/=18 months by 15%. Only with large meta-analyses did the addition of chemotherapy achieve a statistically significant improvement in median survival. Currently there is no means of identifying which patients will benefit from adjuvant chemotherapy, but nitrosoureas and temozolomide are well tolerated in most patients, justifying the administration of adjuvant chemotherapy to all newly diagnosed patients with malignant glioma.
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PMID:Benefits of adjuvant chemotherapy in high-grade gliomas. 1476 79

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

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is a major determinant of methylating anticancer drug resistance. Inactivation of MGMT by pseudosubstrate inhibitors, such as O(6)-benzylguanine (O(6)BG), sensitizes tumor cells to O(6)-alkylating agents. However, systemic administration of O(6)BG causes depletion of MGMT in all tissues of the body. Therefore, dose reduction of O(6)-alkylating drugs administered together with O(6)BG is required in order to avoid unwished toxic side effects. To attenuate the increased systemic toxicity caused by MGMT inhibitors, local MGMT inactivation would be desirable. Here, we report on intracerebral treatment with O(6)BG of a patient suffering from glioblastoma. O(6)BG was administered weekly in the tumor cavity by means of an Ommaya reservoir. This application was well tolerated. Concomitant treatment with temozolomide (Temodal) was associated with transient tumor stabilization without detectable side effects. Although evidence is still lacking that local O(6)BG administration caused MGMT to be depleted in the residual tumor, the trial shows that intracerebral treatment with O(6)BG is feasible. It might be a safe strategy for improving glioma therapy by treatment with temozolomide (and presumably also other O(6)-alkylating drugs) concomitant with O(6)BG without augmenting drug-induced systemic side effects.
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PMID:Local intracerebral administration of O(6)-benzylguanine combined with systemic chemotherapy with temozolomide of a patient suffering from a recurrent glioblastoma. 1703 55

The oral alkylating agent, temozolomide (Temodal: TMZ), is the only anticancer drug that has been shown in a phase III study to improve survival in glioblastoma (GBM) when administered with concomitant radiotherapy. Pharmacokinetic studies have documented relatively high concentrations of TMZ in brain tumors and cerebrospinal fluid (20-40% of the area under the plasma concentration curve), and other studies have demonstrated that TMZ is effective for treatment of various brain tumors, including recurrent and newly diagnosed glioma, primary CNS lymphoma, metastatic melanoma, and neuroblastoma. Molecular markers that predict a favorable response to TMZ plus concomitant radiotherapy include methylguanine methyltransferase (MGMT) promoter methylation patients with GBM and chromosome 1p/19q deletion in patients with anaplastic oligodendroglioma or low-grade glioma. Myelosuppression, nausea and constipation are relatively frequent in patients undergoing treatment with TMZ, and prophylaxis against Pneumocystis carinii pneumonia should be instituted. This article will summarize and discuss these issues as well as review ongoing and anticipated studies of TMZ in combination with other anti-cancer therapies.
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PMID:[Temozolomide: Temodal]. 1834 14


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