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)

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

A rapid and systematic review of the effectiveness and cost-effectiveness of temozolomide in the treatment of recurrent malignant glioma was commissioned by the NHS HTA Programme on behalf of NICE. The full report has been published elsewhere. This paper summarizes the results for the effectiveness of temozolomide in people with recurrent glioblastoma multiforme and anaplastic astrocytoma. The review was conducted using standard systematic review methodology involving a systematic literature search, quality assessment of included studies with systematic data extraction and data synthesis. One randomized controlled trial and four uncontrolled studies were identified for inclusion. The key results were that temozolomide may increase progression-free survival but has no significant impact on overall length of survival. The main effect from temozolomide may have been in those patients who had not received any prior chemotherapy regimens, however further randomized controlled trials are required to confirm this suggestion. Temozolomide appears to produce few serious adverse effects and may also have a positive impact on health-related quality of life. Overall the evidence-base is weak and few strong conclusions can be drawn regarding the effectiveness of temozolomide. Large, well-designed randomized controlled trails conducted in a wider patient population are needed.
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PMID:A rapid and systematic review of the effectiveness of temozolomide for the treatment of recurrent malignant glioma. 1187 May 26

Brain tumours comprise only 2% of all adult cancers, but they are among the most debilitating malignant diseases. Temozolomide, an alkylating agent that can be administered orally, has been approved for the treatment of recurrent malignant glioma on a daily schedule for 5-day cycles. Continuous administration schedules with a higher dose intensity are being explored, but an improvement in efficiency remains to be shown. The benefit from temozolomide given as a single agent in recurrent disease will be several weeks at best. This drug is therefore now undergoing clinical testing as neoadjuvant chemotherapy or with concomitant radiotherapy in patients with newly diagnosed glioma. Several phase I trials are investigating the combination of temozolomide with other agents active against brain tumours. This review briefly summarises the pharmacological background and clinical development of temozolomide and focuses on current and future clinical exploration of this drug for the treatment of brain tumours.
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PMID:Current and future developments in the use of temozolomide for the treatment of brain tumours. 1190 10

Temozolomide (TMZ) is a newly approved alkylating agent for the treatment of malignant gliomas. To investigate resistance mechanisms in a multidrug therapeutic approach, a TMZ-resistant human glioma cell line, SF188/TR, was established by stepwise exposure of human SF188 parental cells to TMZ for approximately 6 months. SF188/TR showed 6-fold resistance to TMZ and cross-resistance to a broad spectrum of other anticancer agents that included 3-5-fold resistance to melphalan (MEL), gemcitabine (GEM), paclitaxel (PAC), methotrexate (MTX), and doxorubicin (DOX), and 1.6-2-fold resistance to cisplatin (CDDP) and topotecan (TPT). Alkylguanine alkyltransferase (AGT) activity was increased significantly in the resistant cell line compared with the parental cell line (P<0.05), whereas no significant differences occurred in the cellular uptake of TMZ and PAC between resistant and parental cells. Depletion of AGT by O(6)-benzylguanine significantly increased the cytotoxicity of TMZ in both the sensitive and resistant cell lines, but did not influence the cytotoxicity of the other drugs tested. Treatment with TMZ caused SF188 cells to accumulate in S phase, whereas SF188/TR cells were unaffected. Expression of Bcl-2 family members in SF188/TR cells compared with SF188 cells indicated that the pro-apoptotic proteins (i.e. Bad, Bax, Bcl-X(S)) were reduced 2-4-fold in the resistant cell line, whereas the anti-apoptotic proteins Bcl-2 and Bcl-X(L) were expressed at similar levels in both cell lines. In conclusion, the mechanism of resistance of SF188/TR cells to TMZ involved increased activity of AGT, a primary resistance mechanism, whereas the broad cross-resistance pattern to other anticancer drugs was due to a common secondary resistance mechanism related to alterations in the relative expression of the pro-apoptotic and anti-apoptotic proteins.
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PMID:Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. 1196 May 98

Oligodendroglial tumors (OD) constitute a specific type of glioma, with a better prognosis than astrocytic tumors of similar grade. OD are sensitive to chemotherapy, with 60-65% of patients responding to PCV chemotherapy and a median response duration of 1-1.5 years. This holds for both low- and high-grade OD. Despite this high response rate, most if not all patients are ultimately relapsing, requiring improvement of treatment. The presence of chromosomal lesions on the loci 1p36 and 19q13.3 is related to a favorable response to both chemotherapy and radiation therapy. In the near future molecular analysis will become an important tool to identify glial tumors that are likely to respond to treatment and will be used to select patients for clinical trials. Temozolomide appears to be a promising drug in OD.
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PMID:New perspectives for the diagnosis and treatment of oligodendroglioma. 1211 2

Temozolomide is an imidazotetrazine with a mechanism of action and efficacy similar to dacarbazine (DTIC). However, it differs from DTIC in that it can be taken orally, degrades spontaneously to an active metabolite and penetrates the blood-brain barrier. It is well tolerated, making it a suitable candidate for combination chemotherapy. Trials to date have focussed on its activity in advanced metastatic melanoma and high-grade malignant glioma. Investigations into other indications, in particular solid tumors with central nervous system metastases, are ongoing. Studies of new drug schedules and of drugs to ameliorate temozolomide resistance offer the prospect of increased efficacy.
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PMID:Temozolomide: a novel oral alkylating agent. 1211 20

Temozolomide (TZM) is a novel methylating agent currently under investigation for treatment of recurrent high-grade gliomas. Although TZM generates a wide spectrum of methyl adducts, its cytotoxicity has been attributed to mismatch repair (MR)-mediated processing of O(6)-methylguanine:T mispairs. N3-methyladenine and N7-methylguanine adducts are promptly repaired by the base excision repair system, unless a poly(ADP-ribose) polymerase (PARP) inhibitor is combined to TZM. In this case, the repair process of N-methylpurines cannot be completed and the deriving DNA strand breaks contribute to cytotoxicity. In this study, we investigated the influence on cell growth and cell cycle of treatment with TZM + PARP inhibitor in glioma cells characterized by different susceptibility to TZM. The results indicated that PARP inhibitor increases growth inhibition induced by TZM in either p53-wild-type or p53-mutant glioblastoma cells, as early as 24 h after drug exposure. The enhancing effect exerted by PARP inhibitor was particularly evident in glioma cells characterized by a defective expression of MR, since these cells are tolerant to O(6)-methylguanine damage and show low sensitivity to TZM. In O(6)-alkylguanine-DNA alkyltransferase (OGAT)-deficient and MR-proficient tumor cells bearing wild-type p53, the drug combination markedly reduced cell accumulation in the G(2)/M phase of cell cycle and induction of the G(2) checkpoint regulator Chk1 kinase. In short-term cultures of glioma cells derived from surgical specimens, PARP inhibitor enhanced chemosensitivity to TZM and this effect was especially evident in OGAT-proficient tumors. Thus, a pharmacological strategy based on the interruption of N-methylpurine repair might represent a novel strategy to restore or increase glioma sensitivity to TZM.
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PMID:Poly(ADP-ribose) polymerase inhibitor increases growth inhibition and reduces G(2)/M cell accumulation induced by temozolomide in malignant glioma cells. 1223 42

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

Temozolomide is a new cytotoxic alkylating agent that has recently been approved in Portugal for the treatment of recurrent high-grade glioma. From September 1999 to March 2001, 16 patients with recurrent glioblastoma multiforme who had prior nitrosurea-based chemotherapy [procarbazine, carmustine, vincristine (PCV)] were given temozolomide 150-200 mg/m2/day for 5 days every 28-day cycle. The estimated 1-year survival rate was 16% and the median overall survival was 6.5 months. Despite the small sample size, the overall survival achieved with temozolomide was similar to that of other reports. These promising data suggest that randomized trials should be undertaken to assess its use in first-line therapy its inclusion in combined chemotherapy regimes and its effectiveness with concurrent radiotherapy.
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PMID:Temozolomide in second-line treatment after prior nitrosurea-based chemotherapy in glioblastoma multiforme: experience from a Portuguese institution. 1239 15


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