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)

Penicillamine is an oral agent used to treat intracerebral copper overload in Wilson's disease. Copper is a known regulator of angiogenesis; copper reduction inhibits experimental glioma growth and invasiveness. This study examined the feasibility, safety, and efficacy of creating a copper deficiency in human glioblastoma multiforme. Forty eligible patients with newly diagnosed glioblastoma multiforme began radiation therapy (6000 cGy in 30 fractions) in conjunction with a low-copper diet and escalating doses of penicillamine. Serum copper was measured at baseline and monthly. The primary end point of this study was overall survival compared to historical controls within the NABTT CNS Consortium database. The 25 males and 15 females who were enrolled had a median age of 54 years and a median Karnofsky performance status of 90. Surgical resection was performed in 83% of these patients. Normal serum copper levels at baseline (median, 130 microg/dl; range, 50-227 microg/dl) fell to the target range of <50 microg/dl (median, 42 microg/dl; range, 12-118 microg/dl) after two months. Penicillamine-induced hypocupremia was well tolerated for months. Drug-related myelosuppression, elevated liver function tests, and skin rash rapidly reversed with copper repletion. Median survival was 11.3 months, and progression-free survival was 7.1 months. Achievement of hypocupremia did not significantly increase survival. Although serum copper was effectively reduced by diet and penicillamine, this antiangiogenesis strategy did not improve survival in patients with glioblastoma multiforme.
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PMID:Phase 2 trial of copper depletion and penicillamine as antiangiogenesis therapy of glioblastoma. 1605 99

The purpose of this study was to determine the response to CPT-11 administered every three weeks to adults with progressive malignant glioma, treated with or without enzyme-inducing antiepileptic drug (EIAED) therapy, at the recommended phase 2 dose determined from a previous phase 1 study. Adult patients age 18 or older with a KPS of 60 or higher who had measurable recurrent grade III anaplastic glioma (AG) or grade IV glioblastoma multiforme (GBM) were eligible. No more than one prior chemotherapy was allowed, either as adjuvant therapy or for recurrent disease. The CPT-11 dose was 350 mg/m(2) i.v. every three weeks in patients not on EIAED and 750 mg/m(2) in patients on EIAED therapy. Patients with stable or responding disease could be treated until tumor progression or a total of 12 months of therapy. The primary end point of the study was to determine whether CPT-11 could significantly delay tumor progression, using the rate of six-month progression-free survival (PFS-6). The trial was sized to be able to discriminate between a 15% and 35% rate for the GBM group alone and between a 20% and 40% rate for the entire cohort. There were 51 eligible patients, including 38 GBM and 13 AG patients, enrolled. The median age was 52 and 42 years, respectively. PFS-6 for the entire cohort was 17.6%. PFS-6 was 15.7% (95% confidence interval [CI], 0.07-0.31) for the GBM patients and 23% (95% CI, 0.07-0.52) for AG patients. Toxicity for the group included diarrhea and myelosuppression. We conclude that the recommended phase 2 dose of CPT-11 for patients with or without EIAED was ineffective on this schedule, in this patient population.
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PMID:A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study. 1653 78

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

CPT-11 is a potent inhibitor of topoisomerase I and has shown antitumor activity in brain xenografts and in clinical trials in recurrent/progressive malignant glioma. VM-26 and VP-16 are topoisomerase II inhibitors and have also shown activity in phase II trials. We performed a phase II trial of intravenous CPT-11 (125 mg/m2) followed 24 h later by VM-26 (125 mg/m2). VP-16 (125 mg/m2) was later substituted for VM-26 due to drug shortage. For patients on anticonvulsants, the starting dose for all drugs was 150 mg/m2. Drugs were given weekly for 3 weeks followed by 1-week rest. Twenty-five patients were entered into the study. Three patients (12%) had improvement in CAT/MRI brain scans (95% confidence interval 3-31%). Fatigue and myelosuppression, mainly leukopenia, were the main toxicities. This combination of the topoisomerase I inhibitor CPT-11 followed by the topoisomerase II inhibitor, VM-26 or VP-16, has shown modest antitumor activity comparable to that reported for each drug singly. Myelosuppression is the main toxicity when topoisomerase I and II inhibitors are combined together.
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PMID:Clinical trial of CPT-11 and VM-26/VP-16 for patients with recurrent malignant brain tumors. 1705 17

Reports suggest reasonable efficacy and minimal myelosuppression from combination imatinib and hydroxyurea for recurrent malignant glioma. We retrospectively reviewed 16 patients treated with this regimen who were evaluable for toxicity; 14 were also evaluable for response. The incidence of grade 3-4 hematologic toxicity was 25%. The best radiographic response, by Macdonald criteria, was partial response (PR) in three patients (21%), stable disease (SD) in four (29%), and progressive disease (PD) in seven (50%). One patient with a PR developed therapy-limiting hematologic toxicity on day 19 of treatment, progressing to grade 4 on day 64, and persisting until death on day 127 despite discontinuing both drugs. Another patient with PR and two of four patients with SD also developed grade 3 hematologic toxicity. All patients with grade 3-4 hematologic toxicity had disease control (PR or SD) as best radiographic response, whereas none with PD suffered grade 3-4 hematologic toxicity. Combining imatinib with hydroxyurea is effective in some patients with malignant glioma. However, myelosuppression can persist for months after discontinuing the regimen, precluding further chemotherapy. Disease control may also correlate with hematologic toxicity (p = 0.08), suggesting that glioma and marrow stem cells may share a common sensitivity to this chemotherapy regimen.
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PMID:Myelosuppression in patients benefiting from imatinib with hydroxyurea for recurrent malignant gliomas. 1759 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

The temozolomide is a promising orally cytotoxic agent used in malignant glioma. The survival curve improvement after drug administration appears to be statistically significant. The review of temozolomide side effects is carried out by search on literature data found on web and is divided on the 4 grades of toxicity according to the National Cancer Institute Common Toxicity Criteria, version 2.0. The adverse effects related with TMZ administration are divided in three categories: myelosuppression, non haematologic toxicity, and infections. The main adverse effect is the myelosuppression that appears to be rather low and reversible as well as the vomiting or nausea. The different schedules of administration are analysed. The frequency of concomitant infections is underlined. In particular, if available, the relationship between temozolomide and other cytotoxic agents or anticonvulsivant drugs is analysed to clarify the possibility of increase of toxicity. The temozolomide is used also in children but the toxicity could be more frequent.
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PMID:The safety of the temozolomide in patients with malignant glioma. 1869 Sep 31

Radiotherapy (RT) and concomitant/adjuvant therapy with temozolomide (Temodar) is a common treatment regimen for children and adults with glioma. Although temozolomide is generally well tolerated with temporary myelosuppression as the primary dose-limiting toxicity, irreversible bone-marrow aplasia after treatment with temozolomide has been reported. We report the case of an adolescent patient with a high-grade glioma who, after >2 years of event-free survival, underwent successful bone marrow transplantation for treatment of temozolomide-induced severe aplastic anemia (SAA).
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PMID:Bone marrow transplantation for severe aplastic anemia secondary to temozolomide. 1881 80

Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) which have a combined incidence of 5-8/100,000 population, represent the most common primary central nervous system tumors. The treatment outcomes even with aggressive approach including surgery, radiation therapy and chemotherapy are dismal with median reported survival is less than 1 year. Temozolomide is a new drug which has shown promise in treating malignant gliomas and other difficult-to-treat tumors. This drug is a per os (p.o) imidazotetrazine second-generation alkylating agent which represents the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. The efficacy of temozolomide was tested in vitro studies and has demonstrated schedule-dependent antitumor activity against highly resistant malignancies, including high-grade glioma (HGG). In addition, in clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Moreover, preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O(6)-alkylguanine alkyltransferase to overcome resistance to chemotherapy in malignant glioma and malignant metastatic melanoma. At the present time temozolomide is approved in the United States for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy. Temozolomide's characteristics which make it a candidate for a wide range of clinical testing to evaluate the potential of combination treatments in different tumor types are its predictable bioavailability and minimal toxicity. An overview of the mechanism of action of temozolomide and a summary of results from more important randomized controlled clinical trials in high grade gliomas are presented here.
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PMID:Temozolomide with radiation therapy in high grade brain gliomas: pharmaceuticals considerations and efficacy; a review article. 1938 85

Thrombocytopenia related intracerebral hemorrhage (ICH) secondary to chemotherapy induced myelosuppression can be very difficult to manage and may result in the death of the patient. We present the case of a 26-year-old male suffering a fatal ICH in the context of treatment of a high grade glioma with temozolomide. The clinician should be aware that a dose dependent severe and possible irreversible myelotoxicity can occur with temozolomide treatment resulting in substantial morbidity.
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PMID:Intracerebral hemorrhage secondary to thrombocytopenia in a patient treated with temozolomide. 2043 32


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