Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among methylating agents of clinical interest, temozolomide is a novel antitumor compound that has raised particular interest due to its acceptable safety profile and activity against tumors poorly responsive to conventional chemotherapy, such as malignant glioma and metastatic melanoma. Moreover, the drug has recently shown promising antitumor activity in a patient affected by primary brain lymphoma and is currently under phase II clinical trials for leptomeningeal metastases from leukemia and lymphoma or for brain metastases from lung and breast cancers. The antitumor activity of TMZ, that generates different types of methyl adducts (70% N7-methylguanine, 10% N3-methyladenine and 9% O6-methylguanine), has been mainly attributed to the formation of O6-methylguanine adducts. Indeed, tumor cell susceptibility to TMZ is strongly affected by the functional status of DNA repair systems, involved either in the removal of methyl adducts from O6G or in the apoptotic signaling triggered by O6-methylG:T mispairs. This review will focus on the different pharmacological strategies aimed at overcoming tumor resistance to TMZ such as new formulations of the drug or dosing schedules, and combined treatments with other chemotherapeutic agents, modulators of DNA repair systems, or gene therapy. The potential use of N3-methyladenine selective agents in the case of tumors tolerant to O6-methylguanine will be also discussed.
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PMID:Pharmacological strategies to increase the antitumor activity of methylating agents. 1205 67

The aim of the study was to evaluate the activity of glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R) and superoxide dysmutase (SOD-1) in the single brain metastases. The activity of the GSH-Px was evaluated with the use of spectrophotometry, GSSG-R was evaluated basing on the method of Mize and Langdon and SOD-1 with Sykes et al. method. The examinations were carried out in 36 specimens (10 specimens of healthy brain tissue, 12 specimens of brain metastases, 14 specimens of glioma multiforme). The statistical analysis revealed significant increase (p < 0.001) of GSH-Px and GSSG-R activity within the single brain metastases in comparison with the healthy brain tissue.
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PMID:[Activity of glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R) and superoxide dismutase (SOD-1) in single brain metastasis]. 1223 89

In the United States, tumors of the central nervous system remain the third leading cancer-related cause of death in young adults with a median survival time of < 1 year. A recent case study suggested that Capecitabine (a novel, fluoropyrimidine prodrug) may be effective in the treatment of brain metastases. Pharmacogenomic studies have correlated the antitumor response to Capecitabine with the expression of the drug metabolizing enzymes thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). In the current study, we examined TP and DPD expression in normal human brain tissues and in glioblastoma multiforme, the most common and malignant type of brain tumor. Because previous reports suggest a tumor necrosis factor (TNF)-alpha-mediated increase in TP expression after irradiation (a current standard of care for glioblastoma multiforme), we also examined the effect of irradiation on the expression of TP, DPD, and TNF-alpha in both irradiated and lead-shielded contralateral U87MG glioma xenografts within the same animal. Expression levels were determined using real-time quantitative PCR as described previously. Results demonstrate an approximately 70-fold increase in TP mRNA levels 4 days after irradiation, relative to initial control levels. Interestingly, TP mRNA in the lead-shielded tumors (contralateral to irradiated tumors) increased approximately 60-fold by day 10 relative to initial control levels. Elevated TP levels were sustained for 20 days in irradiated xenografts but began to decrease after 15 days in the shielded/contralateral tumors, returning to baseline by 20 days. TP mRNA levels in normal mouse liver were unaltered, suggesting a tumor-associated effect. TNF-alpha mRNA levels did not increase after irradiation; therefore, mRNA expression of 11 additional cytokines [interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p35, IL-12p40, IL-15, and IFN-gamma] in both the irradiated and shielded xenografts was quantitated. Results demonstrated increased levels of IFN-gamma, IL-10, and IL-1 alpha by 6.3-, 3.7-, and 1.6-fold, respectively, in irradiated tumors only. DPD mRNA levels did not change after irradiation. The tumor-associated induction of TP in irradiated and lead-shielded tumors within the same animal may have significant implications for the combined modality treatment of cancer patients with Capecitabine in conjunction with radiotherapy and may apply to the treatment of distant tumors and or metastatic disease.
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PMID:Induction of thymidine phosphorylase in both irradiated and shielded, contralateral human U87MG glioma xenografts: implications for a dual modality treatment using capecitabine and irradiation. 1248 38

Epileptic seizures are common in patients with cerebral metastases as well as in patients with primary brain tumors. In cancer patients without primary brain tumors or brain metastasis, epileptic seizures may occur due to metabolic or toxic causes, or due to infections. We performed a retrospective analysis from our neurooncological database concerning the occurrence of seizures in patients with primary brain tumors, patients with cerebral metastases and in cancer patients without brain tumors. Patients with low grade gliomas, such as astrocytoma WHO I + II (69%), oligodendroglioma WHO II (50%), and mixed glioma WHO II-III (56%) were more likely to have seizures than patients with anaplastic glioma WHO III (44%), glioblastoma WHO IV (48%) or meningeoma (45%). In patients with brain metastasis, melanoma (67%), cancer of the lung (29%), and gastrointestinal tumors (21%) were the primaries with the highest frequency of seizures. In cancer patients without brain metastases or primary brain tumors, seizures occurred in 4%. In conclusion, the occurrence of epileptic seizures in patients suffering from primary brain tumors, as well as in patients with cerebral metastases, varied within the tumor entity. Therefore, especially in brain tumors where a higher probability of epileptic seizures is expected, they should be taken into account in the care of cancer patients.
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PMID:[The frequency of seizures in patients with primary brain tumors or cerebral metastases. An evaluation from the Ludwig Boltzmann Institute of Neuro-Oncology and the Department of Neurology, Kaiser Franz Josef Hospital, Vienna]. 1252 23

This review summarizes the current status and future prospects for combined modality treatment of primary and metastatic central nervous system malignancies. The laboratory and clinical basis for multimodality therapy, including surgery, ionizing radiation, and drug therapy, are outlined and critically reviewed. The central nervous system diseases discussed include: glioma (low and high grade), brain metastases, and primary central nervous system lymphoma. Collectively, these data suggest a shift favoring combined modality approaches in several of these diseases; however, the incremental gains are indeed modest. The individual practitioner must weigh these with the additional toxicities before making a therapeutic decision for a particular patient. The future direction of combined modality therapy in these diseases will likely revolve around the increased use of molecular diagnostics resulting in the application of targeted therapy. Clearly, such promising innovations must be delineated in the context of continued preclinical studies and controlled clinical trials.
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PMID:Combined modality treatment for central nervous system malignancies. 1290 33

Motexafin gadolinium [gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120] is a radiosensitising agent developed for use in cancer therapy. It is cytotoxic in haematological malignancies by selectively localising in cancer cells that have high rates of metabolism. Motexafin gadolinium inhibits cellular respiration resulting in the production of reactive oxygen species and inducing apoptosis. It is being developed by Pharmacyclics in the US. Bulk motexafin gadolinium is supplied to Pharmacyclics by the US company, Celanese, through a manufacturing and supply agreement between the two companies. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), the importance of having an agent for the treatment of brain metastases from lung cancer was highlighted. Results of a phase III study were presented that showed that motexafin gadolinium treatment was associated with a delay in time to neurological and neurocognitive progression in lung cancer patients. This was an important finding, as 46.6% of lung cancer patients already have brain metastases at the time of initial diagnosis, compared with only 2.7% of breast cancer patients. Brain metastases are also often the only site of metastatic disease in patients with lung cancer. In December 2002, Pharmacyclics began a phase III trial of motexafin gadolinium in patients with brain metastases (brain cancer in phase table) from lung cancer in the US, Europe, Canada and Australia. The trial is known as the Study of neurologic progression with Motexafin gadolinium And Radiation Therapy (SMART) and will compare whole-brain irradiation with whole-brain irradiation plus motexafin gadolinium in 550 patients. The primary efficacy endpoint is time to neurological progression and the secondary endpoints are survival and neurocognitive function. In January 2003, the US FDA completed its Special Protocol Assessment (SPA) of the SMART trial with a positive result and by June 2003, enrollment had begun. In addition, phase I trials are underway in children with intrinsic pontine glioma and adults with head and neck, lung and pancreatic cancers. A phase II trial is also being conducted in the US in patients with glioblastoma multiforme. Enrollment in this trial has been completed and preliminary results have been reported. Pharmacyclics has completed enrollment and follow-up of adults in its pivotal phase III trial of motexafin gadolinium as a radiation sensitiser for the treatment of brain metastases. The trial was conducted at 35 centres in Europe, Canada and the US. Full results from this initial phase III trial were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Florida, USA, held in May 2002. Pharmacyclics also announced in October 2002, at the 44th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), that motexafin gadolinium significantly prolonged time to neurological progression when added to whole brain radiation therapy and reduced the number of deaths in patients with brain tumour. Pharmacyclics announced in September 2000 that it has initiated two NCI-sponsored phase I trials conducted under a Cooperative Research and Development Agreement (CRADA) between Pharmacyclics and the NCI. The first trial, conducted in patients with stage IIIA non-small cell lung cancer, was designed to determine the safety of two different dosing regimens of motexafin gadolinium during preoperative radiotherapy after induction chemotherapy. The second study was designed to examine the use of motexafin gadolinium in combination with stereotactic Gamma Knife radiosurgery in patients with primary glioblastoma mutiforme. Two phase I clinical trials have also been conducted for the treatment of newly diagnosed glioblastoma multiforme at the UCLA Jonsson Comprehensive Cancer Center, USA. These phase I studies were sponsored by the NCI and were conducted under a CRADA with the NCI. Pharmacyclics has also completed multicentre US phase II clinical trials of motexafin gadolinium fin gadolinium in patients with metastatic tumours of the brain who require whole brain radiotherapy. Motexafin gadolinium is in a phase II trial in patients with lymphomas and multiple myeloma in the US.
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PMID:Motexafin gadolinium: gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120. 1472 95

Gross intracranial hemorrhage associated with brain tumor has been reported to range from 3.6-10%. Brain metastases and malignant glioma are the most frequent underlying pathologies. Intracranial hemorrhage related to meningioma is a rare condition. Subarachnoid hemorrhage, acute subdural hematoma, intratumoral and intraparenchymal hematomas are the most common forms of bleeding associated with meningioma. By contrast, chronic subdural hematoma (cSDH) and intraventricular hemorrhage are seen less frequently. The authors report a very rare case of left fronto-parietal convexity meningioma associated with bilateral cSDH in a patient with history of recent minor head trauma and review the literature on hemorrhage associated with meningiomas.
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PMID:Bilateral chronic subdural hematoma associated with meningioma. Case report and review of the literature. 1497 76

Radiation-induced neoplasms are extremely rare after stereotactic radiosurgery. To date, only 3 cases meet Cahan's criteria in the world literature. We present a fourth case of a radiation-induced neoplasm arising after radiosurgery. The patient is a 43-year-old woman who presented with a right cerebellar anaplastic astrocytoma 64 months after radiosurgery for metastatic melanoma. Initially, 3 brain metastases involving the inferior right temporal (2 tumors) and right frontal regions were treated. Following radiosurgery, the patient underwent whole brain radiotherapy (37.5 Gy). Twenty-two months later, a second radiosurgical procedure was performed for a recurrent right temporal lobe metastasis. The area of cerebellum where the glioma developed received a maximum dose of 7.7 and 1.5 Gy during the 2 procedures, respectively. Support that radiosurgery contributed to the development of this glioma are the tumor's location and the rarity of adult cerebellar astrocytomas. The risk of radiation-induced tumors after radiosurgery is unknown. To better define the incidence of radiation-induced neoplasms after radiosurgery, all potential cases should be presented and discussed in an open, candid fashion.
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PMID:Radiation-induced tumor after stereotactic radiosurgery and whole brain radiotherapy: case report and literature review. 1501 61

Glutamine (Gln) is a growth determinant in neoplastic tissues. We analysed by RT-PCR the expression of mRNAs coding for the human variants of Gln transporters: ASCT2 (system ASC), SNAT1 [ATA1] (system A), SNAT3 [SN1] and SNAT5 [SN2] (system N), in samples of human malignant gliomas WHO grades III/IV (anaplastic astrocytoma and glioblastoma), glioma-derived cell cultures, brain metastases from peripheral organs, and control brain tissue. SNAT3 mRNA showed a 3-5 times stronger expression in gliomas than in metastases or control tissue, and was virtually absent from glioma cultures. Native glioblastoma immunostained positively with anti-SNAT3 antibody. The expression of ASCT2 mRNA, but not SNAT5 or SNAT1 mRNAs, was increased in all neoplastic tissues studied. Hence, increased expression of SNAT3 is a marker of primary malignant gliomas in situ.
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PMID:Increased expression of a glutamine transporter SNAT3 is a marker of malignant gliomas. 1509 55

The EORTC Brain Tumor Group (BTG) is dedicated to clinical research of neoplasms of the brain. In the past years the BTG has carried out phase II and phase III trials on glial tumors, brain metastases and primary CNS lymphomas. Future studies will investigate novel drugs in combination with chemo-radiotherapy in glioblastoma multiforme, radiotherapy in meningioma, and chemotherapy in medulloblastoma. The BTG will also start a new phase III trial on newly diagnosed low-grade glioma comparing radiotherapy to temozolomide. In all our trials translational research is getting more and more important, often this is one of the most important ways to get useful conclusions from clinical trials. The wide recognition of the importance of translational research for clinical trials and in particular with targeted therapies implies that this type of research will become a mandatory element in many of our future trials.
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PMID:Current and future trials of the EORTC brain tumor group. 1524 13


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