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)

O6-methylguanine-DNA methyltransferase (MGMT) plays a major role in repairing DNA damage from alkylating agents. By removing alkyl groups from the O6-position in guanine, MGMT can prevent G:C to A:T transition mutations, a type of variation frequently involving TP53 mutations in brain tumors. Promoter hypermethylation of CpG islands in tumor-related genes can lead to their transcriptional inactivation, and this epigenetic mechanism has been shown to participate in MGMT silencing in some cancers, including those affecting the nervous system. Accordingly, a link between both genetic and epigenetic anomalies may exist in these neoplasms. To determine the relevance of defective MGMT function due to aberrant methylation in relation to the presence of TP53 mutations, we studied 469 nervous system tumors (including all major histological subtypes) for MGMT promoter methylation and TP53 mutations at exons 5-8. Overall, aberrant methylation occurred in 38% of the samples (180/469), with values higher than 50% in the more malignant forms such as glioblastomas and anaplastic gliomas including those with astrocytic, oligodendroglial and ependymal differentiation. In contrast, the non-glial tumors displayed an overall aberrant MGMT promoter methylation of 26%, even though this group includes highly malignant tumors such as neuroblastomas, medulloblastomas and brain metastases. Overall, TP53 mutations were found in 25% of the methylated MGMT tumors (45/180), whereas only 10% of the unmethylated MGMT tumors (30/289) showed TP53 changes (P < 0.001). G:C to A:T changes occurred at CpG sites in 9% of methylated tumors, and in 0.7% of the unmethylated samples. This type of transition at non-CpG dinucleotides was also more frequent in the tumors with aberrant MGMT methylation (5%) than the unmethylated tumors (0.7%). These data suggest that MGMT silencing as a result of promoter hypermethylation may lead to G:C to A:T transition mutations in the TP53 gene of some histological nervous system tumor subtypes.
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PMID:Hypermethylation of the DNA repair gene MGMT: association with TP53 G:C to A:T transitions in a series of 469 nervous system tumors. 1545 Apr 1

In this paper, we studied factors related to long-term survival after gamma knife radiosurgery (GKS) for primary and metastatic brain tumors. We examined all cases of brain metastases and malignant glioma treated with GKS between September 1994 and December 1998. All patients with survival exceeding 2 years were studied retrospectively using prospectively acquired data. A total of 22 patients, with an average age of 56, were identified, which accounts for 11% of the total patients treated during this time interval. Seventeen of 22 are still alive with a mean follow-up of 48 months. Sixteen patients had metastatic tumors, whereas 6 had a malignant glioma. Thirteen of 15 patients with metastases had a controlled primary site, and the other 2 patients did not have a primary site identified. These 2 patients were among the 3 that died during the follow-up period. Fourteen patients developed symptomatic radiation necrosis by MRI criteria with 4 confirmed by biopsy. Quality-of-life factors were assessed in 20 of 22 patients using a modified Spitzer scale, which showed a high level of functioning in all of the long-term survivors (mean score 8.65 of 10), and only 1 patient had a Karnofsky Performance Score of less than 70. We conclude that radiosurgery provides a noninvasive and effective way of controlling brain tumors, while preserving quality of life.
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PMID:Long-term survival after gamma knife radiosurgery for primary and metastatic brain tumors. 1559 6

Stereotactic radiosurgery is a radiation technique that uses a high radiation dose focused on a stereotactic defined intracranial target in single fraction with high precision. In the 1980s, linear accelerators were introduced as a tool for radiosurgery beneath the already accepted gamma unit. Technique and mechanical precision of LINACs have become equal to the gamma unit and LINAC radiosurgery became more and more used recently. From January 1996 to August 2003 we have treated 237 patients with LINAC radiosurgery. A combination of the University of Florida system and the X Knife System, developed by Radionics, was used in all patients. A number of 110 patients had 161 brain metastases treated, whereas the local tumor control rate was 89.4%. The 1-year survival rate was 54.9% with a median survival of 54 weeks. In 55 patients we have treated 57 meningiomas, mostly located at the skull base (37 out of 55 patients). Local tumor control rate in our patients with skull base meningiomas at 5-year follow up was 97.2%. In this time period, we have also treated acoustic schwannoma, glioma, pituitary adenoma, arteriovenous malformations and patients with trigeminal neuralgia. LINAC radiosurgery has become a daily tool in neurosurgery and changed treatment strategies especially in the treatment of brain metastases and skull base meningiomas towards a less aggressive and multimodality approach. It is not only an alternative to open surgery, but also a very effective adjuvant treatment modality in many neuro-oncological patients, which helps us to enhance tumor control rate, minimize morbidity and increase postoperative quality of life.
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PMID:Linac radiosurgery as a tool in neurosurgery. 1572 39

Chemotherapy for the treatment of brain metastases arising from non-small cell lung cancer (NSCLC) has been limited by poor efficacy and high toxicity. Especially in heavily pretreated patients with brain metastases, further chemotherapy is known to be extraordinarily difficult. Expression of vascular endothelial growth factor is necessary but not sufficient for production and growth of brain metastasis. Most current preclinical experiments evaluate antiangiogenic drugs used singly or in combination with other antiangiogenic drugs and/ or cytotoxic drugs. Cerebral edema is responsible for significant morbidity and mortality in patients harboring malignant gliomas. In preclinical experiments, cyclooxygenase (COX) -2 plays an important role in the formation of brain edema. Glioma-infiltrating microglia are a major source of PGE2 production through the COX-2 pathway and support the use of COX-2 inhibitors as possible alternatives to glucocorticoids in the treatment of peritumoral edema in patients with malignant brain tumors. Here we report a case of lung cancer patient with brain metastases who had been treated with chemotherapy and whole-brain radiation therapy (WBRT). He was treated with thalidomide, celceoxib and gemcitabine, after which brain metastases have almost completely disappeared. He tolerated extremely well. This combination may play an important role for patients with NSCLC and brain metastases.
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PMID:[A case report of chemotherapy with thalidomide, celecoxib and gemcitabine in the treatment of patients with brain metastases from lung cancer]. 1622 82

The blood-brain barrier (BBB) is of pivotal importance to maintain homeostasis of the CNS, as it closely regulates the composition of the interstitial fluid in the brain. Unfortunately, malignancies that grow within the CNS may evade chemotherapeutic drugs using the same barrier, making this disease refractory to most chemotherapy regimens. This review will outline the impact of the BBB in brain cancer and discuss the efforts that have been made to enhance the drug exposure of brain tumors. Although this review will focus on the role of the BBB in primary brain cancer (malignant glioma), its impact on brain metastases will also be briefly discussed.
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PMID:Blood-brain barrier and chemotherapeutic treatment of brain tumors. 1689 47

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

High-grade glioma is a devastating disease that leaves the majority of its victims dead within 2 years. To meaningfully increase survival, a trimodality approach of surgery, radiation, and chemotherapy is needed. Carmustine (1,3-bis (2-chloroethyl)-1-nitrosourea) is a nitrosourea alkylating agent that exerts its antitumor effect by akylating DNA and RNA. Systemic administration of nitrosoureas as a single agent or as part of procarbazine/3-cyclohexyl-1-nitroso-urea/vincristine has demonstrated little efficacy in the treatment of high-grade glioma. The development of carmustine wafers (Gliadel((R)) Wafer) as a method for controlled released delivery of carmustine from biodegradable polymer wafers enhances the therapeutic ratio by fully containing the drug within the confines of the brain tumor environment while minimizing systemic toxicities. Preclinical and clinical studies have proven the safety and efficacy of Gliadel in the management of glioblastoma. From these results, Gliadel is currently approved for use in patients with recurrent glioblastoma as an adjunct to surgery and in newly diagnosed patients with high-grade glioma as an adjunct to surgery and radiation. Other promising advances in the use of locally delivered chemotherapy for CNS malignancies, including Gliadel for brain metastases and combination therapies with systemic or biologic agents, are discussed.
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PMID:Carmustine wafers: localized delivery of chemotherapeutic agents in CNS malignancies. 1836 83

The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX) on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally) 24 hours before human ovarian carcinoma (SKOV3), small cell lung carcinoma (LX-1 SCLC), and glioma (UW28, U87MG, and U251) tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0%) of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive) infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.
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PMID:Cyclophosphamide enhances human tumor growth in nude rat xenografted tumor models. 1917 3

The first Klatzo-Lecture pays homage to an exceptional academician, scientist and teacher. The author spent nearly 1 year in Klatzo's laboratory at the NHI in Bethesda, and the first part of results presented here originate directly from this collaboration. It was shown that following cortical injury, movement of edema fluid into the tissue occurs by bulk flow, and that the driving force is a small tissue pressure gradient. Resolution of edema fluid is achieved by clearance into the ventricular and subarachnoid CSF, is enhanced in the presence of pressure gradients and is supported by re-absorption into capillaries. Using appropriate techniques, the formation rate as well as clearance of edema into CSF and tissue resorption could be determined in human brain metastases and malignant gliomas. Three examples of clinical applications based on the discussed mechanisms are presented: a. Fluorescence-guided surgery of gliomas is based on the accumulation of 5-ALA in tumour cells; there being enzymatically converted to PP-IX, a compound with deep red fluorescence. This fluorescence is used for the more accurate surgical removal of gliomas. b. Radioimmunotherapy of gliomas uses an anti-tenascin antibody, coupled with a nuclide, administered postoperatively into the tumour cavity, from where it diffuses into tissue, couples to the receptor at the glioma cells. Then the isotope destroys the tumour cells. c. Convection-enhanced delivery is based on the interstitial infusion of an appropriate cytotoxic drug into the white matter at low pressure. Thus, the method employs bulk flow, distributes a drug in a larger tissue volume and eventually achieves drug concentrations greater than systemic levels. Experimental studies and clinical results are presented for all three clinical applications.I am very grateful to Z. Czernicki and the organizing group for being offered the great honour of presenting the first Igor Klatzo Lecture. In this report first previous results of bulk flow and diffusion in the development and resolution of brain edema will be revisited, then some recent examples will be shown as to how this knowledge of diffusion and bulk flow can be transferred into clinical applications.A great part of the work on bulk flow and diffusion was done during a stay in I. Klatzo's laboratory in Bethesda in 1973/1974 (Fig. 1). Since then a long collaboration developed with I. Klatzo and M. Spatz. Due to given limits, I will concentrate on the studies of our group. Unfortunately it will not be possible to mention all the important groups who have contributed by essential studies.
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PMID:Bulk flow and diffusion revisited, and clinical applications. 1981 13

Malignant primary glial and secondary metastatic brain tumors represent distinct pathological entities. Nevertheless, both tumor types induce profound angiogenic responses in the host brain microvasculature that promote tumor growth. We hypothesized that primary and metastatic tumors induce similar microvascular changes that could function as conserved angiogenesis based therapeutic targets. We previously isolated glioma endothelial marker genes (GEMs) that were selectively upregulated in the microvasculature of proliferating glioblastomas. We sought to determine whether these genes were similarly induced in the microvasculature of metastatic brain tumors. RT-PCR and quantitative RT-PCR were used to screen expression levels of 20 candidate GEMs in primary and metastatic clinical brain tumor specimens. Differentially regulated GEMs were further evaluated by immunohistochemistry or in situ hybridization to localize gene expression using clinical tissue microarrays. Thirteen GEMs were upregulated to a similar degree in both primary and metastatic brain tumors. Most of these genes localize to the cell surface (CXCR7, PV1) or extracellular matrix (COL1A1, COL3A1, COL4A1, COL6A2, MMP14, PXDN) and were selectively expressed by the microvasculature. The shared expression profile between primary and metastatic brain tumors suggests that the molecular pathways driving the angiogenic response are conserved, despite differences in the tumor cells themselves. Anti-angiogenic therapies currently in development for primary brain tumors may prove beneficial for brain metastases and vice versa.
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PMID:Vascular gene expression patterns are conserved in primary and metastatic brain tumors. 2006 14


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