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1.
J Neurooncol ; 161(3): 605-615, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36648586

RESUMO

PURPOSE: Lower-grade glioma (LGG) is rare among patients above the age of 60 ("elderly"). Previous studies reported poor outcome, likely due to the inclusion of isocitrate dehydrogenase (IDH) wildtype astrocytomas and advocated defensive surgical and adjuvant treatment. This study set out to question this paradigm analyzing a contemporary cohort of patients with IDH mutant astrocytoma and oligodendroglioma WHO grade 2 and 3. METHODS: Elderly patients treated in our department for a supratentorial, hemispheric LGG between 2009 and 2019 were retrospectively analyzed for patient-, tumor- and treatment-related factors and progression-free survival (PFS) and compared to patients aged under 60. Inclusion required the availability of subtype-defining molecular data and pre- and post-operative tumor volumes. RESULTS: 207 patients were included, among those 21 elderlies (10%). PFS was comparable between elderly and younger patients (46 vs. 54 months; p = 0.634). Oligodendroglioma was more common in the elderly (76% vs. 46%; p = 0.011). Most patients underwent tumor resection (elderly: 81% vs. younger: 91%; p = 0.246) yielding comparable residual tumor volumes (elderly: 7.8 cm3; younger: 4.1 cm3; p = 0.137). Adjuvant treatment was administered in 76% of elderly and 61% of younger patients (p = 0.163). Uni- and multi-variate survival analyses identified a tumor crossing the midline, surgical strategy, and pre- and post-operative tumor volumes as prognostic factors. CONCLUSION: Elderly patients constitute a small fraction of molecularly characterized LGGs. In contrast to previous reports, favorable surgical and survival outcomes were achieved in our series comparable to those of younger patients. Thus, intensified treatment including maximal safe resection should be advocated in elderly patients whenever feasible.


Assuntos
Astrocitoma , Neoplasias Encefálicas , Glioma , Oligodendroglioma , Idoso , Humanos , Astrocitoma/cirurgia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Glioma/genética , Glioma/terapia , Isocitrato Desidrogenase/genética , Isocitratos , Intervalo Livre de Progressão , Estudos Retrospectivos
2.
Neuropathol Appl Neurobiol ; 46(5): 422-430, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31867747

RESUMO

AIMS: DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. PATIENTS AND METHODS: DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the 'conumee' package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. RESULTS: Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. CONCLUSIONS: DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Cromossomos Humanos Par 14/genética , Glioma/genética , Glioma/patologia , Metilação de DNA , Feminino , Humanos , Masculino , Monossomia , Neurocitoma/genética , Neurocitoma/patologia , Oligodendroglioma/genética , Oligodendroglioma/patologia
3.
Neuropathol Appl Neurobiol ; 45(2): 108-118, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30326163

RESUMO

AIMS: Mutations of isocitrate dehydrogenase (IDH)1/2 affect almost all astrocytomas of WHO grade II and III. A subset of IDH-mutant astrocytic tumours progresses to IDH-mutant glioblastoma or presents with the histology of a glioblastoma at first presentation. We set out here to assess the molecular spectrum of IDH-mutant glioblastomas. METHODS: We performed an integrated molecular analysis of a mono-centric cohort (n = 97); assessed through genome-wide DNA methylation analysis, copy-number profiling and targeted next generation sequencing using a neurooncology-tailored gene panel. RESULTS: Of these 97 IDH-mutant glioblastomas, 68 had a glioblastoma at first presentation ('de novo' IDH-mutant glioblastoma) and 29 emerged from a prior low-grade lesion ('evolved' IDH-mutant glioblastoma). Unsupervised hierarchical clustering of DNA methylation data disclosed that IDH-mutant glioblastoma ('de novo' and 'evolved') formed a distinct group separate from other diffuse glioma subtypes. Homozygous deletions of CDKN2A/B were found to be associated with shorter survival. CONCLUSIONS: This study demonstrates DNA methylation patterns in IDH-mutant glioblastoma to be distinct from lower-grade astrocytic counterparts but homogeneous within de novo and evolved IDH-mutant glioblastomas, and identifies CDKN2A as a marker for possible genetic sub-stratification.


Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Glioblastoma/genética , Glioma/patologia , Isocitrato Desidrogenase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrocitoma/genética , Neoplasias Encefálicas/genética , Glioma/genética , Humanos , Pessoa de Meia-Idade , Mutação/genética , Gradação de Tumores/métodos , Adulto Jovem
4.
Biochim Biophys Acta ; 1844(8): 1415-26, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24440405

RESUMO

Glioblastoma, an aggressive brain tumor, has a poor prognosis and a high risk of recurrence. An improved chemotherapeutic approach is required to complement radiation therapy. Gold(I) complexes bearing phosphole ligands are promising agents in the treatment of cancer and disturb the redox balance and proliferation of cancer cells by inhibiting disulfide reductases. Here, we report on the antitumor properties of the gold(I) complex 1-phenyl-bis(2-pyridyl)phosphole gold chloride thio-ß-d-glucose tetraacetate (GoPI-sugar), which exhibits antiproliferative effects on human (NCH82, NCH89) and rat (C6) glioma cell lines. Compared to carmustine (BCNU), an established nitrosourea compound for the treatment of glioblastomas that inhibits the proliferation of these glioma cell lines with an IC50 of 430µM, GoPI-sugar is more effective by two orders of magnitude. Moreover, GoPI-sugar inhibits malignant glioma growth in vivo in a C6 glioma rat model and significantly reduces tumor volume while being well tolerated. Both the gold(I) chloro- and thiosugar-substituted phospholes interact with DNA albeit more weakly for the latter. Furthermore, GoPI-sugar irreversibly and potently inhibits thioredoxin reductase (IC50 4.3nM) and human glutathione reductase (IC50 88.5nM). However, treatment with GoPI-sugar did not significantly alter redox parameters in the brain tissue of treated animals. This might be due to compensatory upregulation of redox-related enzymes but might also indicate that the antiproliferative effects of GoPI-sugar in vivo are rather based on DNA interaction and inhibition of topoisomerase I than on the disturbance of redox equilibrium. Since GoPI-sugar is highly effective against glioblastomas and well tolerated, it represents a most promising lead for drug development. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.


Assuntos
Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glioma/tratamento farmacológico , Ouro/química , Compostos Organofosforados/síntese química , Compostos Organofosforados/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Movimento Celular/efeitos dos fármacos , Glioma/metabolismo , Glioma/patologia , Glutationa/metabolismo , Glutationa Redutase/antagonistas & inibidores , Glutationa Redutase/metabolismo , Humanos , Masculino , Ratos , Ratos Wistar , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo , Células Tumorais Cultivadas
6.
Neuropathol Appl Neurobiol ; 39(7): 831-6, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23521081

RESUMO

AIMS: Combined deletion of the whole chromosomal arms 1p and 19q is a frequent event in oligodendroglial tumours. Recent identification of recurrent mutations in CIC on 19q and FUBP1 on 1p and their mutational patterns suggest a loss of function of the respective proteins. Surprisingly, oligoastrocytomas harbouring identical genetic characteristics regarding 1p/19q codeletion and frequent IDH1/2 mutations have been shown to carry CIC mutations in a significantly lower number of cases. The present study investigates whether epigenetic modification may result in silencing of CIC. METHODS: As IDH1/2 mutation-mediated DNA hypermethylation is a prominent feature of these tumours, we analysed a set of CIC wild-type oligoastrocytomas and other diffuse gliomas with regard to 1p/19q status for presence of CIC-associated CpG island methylation by methylation-specific PCR. RESULTS: Both methylation-specific PCR and subsequent bisulphite-sequencing of selected cases revealed an unmethylated status in all samples. CONCLUSION: Despite the hypermethylator phenotype in IDH1/2 mutant tumours and recent detection of gene silencing particularly on retained alleles in oligodendroglial tumours, hypermethylation of CIC-associated CpG islands does not provide an alternative mechanism of functional CIC protein abrogation.


Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 1 , Ilhas de CpG/genética , Metilação de DNA , Oligodendroglioma/genética , Neoplasias Encefálicas/patologia , Metilação de DNA/genética , Predisposição Genética para Doença , Humanos , Perda de Heterozigosidade/genética , Mutação/genética
7.
Int J Tryptophan Res ; 16: 11786469231153111, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36798537

RESUMO

The vascular niche of malignant gliomas is a key compartment that shapes the immunosuppressive brain tumor microenvironment (TME). The blood-brain-barrier (BBB) consisting of specialized endothelial cells (ECs) and perivascular cells forms a tight anatomical and functional barrier critically controlling transmigration and effector function of immune cells. During neuroinflammation and tumor progression, the metabolism of the essential amino acid tryptophan (Trp) to metabolites such as kynurenine has long been identified as an important metabolic pathway suppressing immune responses. Previous studies have demonstrated that indoleamine-2,3-dioxygenase-1 (IDO1), a key rate-limiting enzyme in tryptophan catabolism, is expressed within the TME of high-grade gliomas. Here, we investigate the role of endothelial IDO1 (eIDO1) expression for brain tumor immunity. Single-cell RNA sequencing data revealed that in human glioma tissue, IDO1 is predominantly expressed by activated ECs showing a JAK/STAT signaling pathway-related CXCL11+ gene expression signature. In a syngeneic experimental glioma model, eIDO1 is induced by low-dose tumor irradiation. However, cell type-specific ablation of eIDO1 in experimental gliomas did not alter frequency and phenotype of tumor-infiltrating T cells nor tumor growth. Taken together these data argue against a dominant role of eIDO1 for brain tumor immunity.

8.
Neuroscience ; 137(4): 1247-57, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16359813

RESUMO

Dehydroepiandrosterone 3-sulfate and other neurosteroids are synthesized in the CNS and peripheral nervous system where they may modulate neuronal excitability by interacting with ligand-gated ion channels. For this modulatory activity, neurosteroids have to be locally released from either neurons or glial cells. We here identify the integral membrane protein ABCC11 (multidrug resistance protein 8) as an ATP-dependent efflux pump for steroid sulfates, including dehydroepiandrosterone 3-sulfate, and localize it to axons of the human CNS and peripheral nervous system. ABCC11 mRNA was detected in human brain by real-time polymerase chain reaction. Antibodies raised against ABCC11 served to detect the protein in brain by immunoblotting and immunofluorescence microscopy. ABCC11 was preferentially found in the white matter of the brain and co-localized with neurofilaments indicating that it is an axonal protein. Additionally, ABCC11 was localized to axons of the peripheral nervous system. For functional studies, ABCC11 was expressed in polarized Madin-Darby canine kidney cells where it was sorted to the apical membrane. This apical sorting is in accordance with the localization of ABCC11 to the axonal membrane of neurons. Inside-out plasma membrane vesicles containing recombinant ABCC11 mediated ATP-dependent transport of dehydroepiandrosterone 3-sulfate with a Km value of 21 microM. This transport function together with the localization of the ABCC11 protein in vicinity to GABAA receptors is consistent with a role of ABCC11 in dehydroepiandrosterone 3-sulfate release from neurons to sites of dehydroepiandrosterone 3-sulfate-mediated receptor modulation. Our findings may provide a basis for the characterization of mutations in the human ABCC11 gene and their linkage with neurological disorders.


Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Axônios/fisiologia , Encéfalo/fisiologia , Sistema Nervoso Central/fisiologia , Resistência a Múltiplos Medicamentos , Sistema Nervoso Periférico/fisiologia , Esteroides/metabolismo , Sulfatos/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Sequência de Aminoácidos , Sequência de Bases , Primers do DNA , Sulfato de Desidroepiandrosterona/metabolismo , Humanos , Dados de Sequência Molecular , Neurônios/metabolismo , Fragmentos de Peptídeos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
9.
Cancer Res ; 53(18): 4189-96, 1993 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-8364914

RESUMO

As in most other tumor types, expression of mutated or phenotypically altered p53 is a common occurrence in head and neck carcinogenesis. Since the prognosis for many head and neck tumor patients is severely affected by the occurrence of multiple primary and secondary tumors, we have analyzed the phenotype and genotype of p53 in squamous and respiratory epithelia either adjacent to or at significant distance from the primary tumors. Many tumor patients showed multifocal overexpression of the p53 protein in a variety of these epithelia. Overexpression of p53 correlated with increased proliferation and dedifferentiation, as demonstrated by immunohistochemistry and in situ hybridization using histone H3 and cytokeratin-specific probes. Polymerase chain reaction-single-strand conformation polymorphism analysis and sequencing of p53 DNA, amplified from these biopsies after immunostaining and microdissection, confirmed and extended these findings. We have identified different mutations in p53 in different tumor-distant epithelia from the same patients. The data indicate that mutation of p53 is an early event in head and neck carcinogenesis, preceding signs of overt neoplasia, and that different mutations in p53 in multiple foci may provide a molecular basis for the development of multiple tumors.


Assuntos
Genes p53 , Neoplasias de Cabeça e Pescoço/genética , Mutação , Neoplasias Primárias Múltiplas/genética , Sequência de Bases , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/patologia , Diferenciação Celular , Divisão Celular , Códon , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imuno-Histoquímica , Dados de Sequência Molecular , Neoplasias Primárias Múltiplas/química , Neoplasias Primárias Múltiplas/patologia , Reação em Cadeia da Polimerase , Proteína Supressora de Tumor p53/análise
10.
Rofo ; 177(1): 114-8, 2005 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-15657829

RESUMO

PURPOSE: Previous studies on intracranial tumors indicate that a high apparent diffusion coefficient (ADC) is due to low cellularity and that lower values indicate a dense, highly cellular tumor. Diffusion is affected by three major factors: cell density, existence and distribution of vasogenic edema, and hypoxic tissue. Therefore, we studied the characteristics of diffusion-weighted magnetic resonance imaging (DWI) in a rat brain C6 glioma during tumor progression. MATERIALS AND METHODS: In male Wistar rats, C6 gliomas were implanted in the caudoputamen. At day 9, 11, 13 and 15 after tumor inoculation, conventional DWI was performed on a 2.35 Tesla small bore MRI unit (Biospec 24/40, BRUKER Medizintechnik, Ettlingen, Germany). RESULTS: On conventional T2-weighted and contrast-enhanced T1-weighted images, all tumors could well be delineated from the surrounding brain tissue and showed significant progression. On DWI, the tumors were isointense or slightly hypointense compared to the surrounding brain. On the ADC maps, the tumors could be well visualized due to increasing ADC values from day 9 to 15. The mean ADC of brain tumor tissue was 0.76 +/- 0.4 x 10 ( - 3) mm (2)/s at day 9 and 0.91 +/- 0.03 x 10 ( - 3) mm (2)/s at day 15. The mean ADC of the normal contralateral caudoputamen was 0.59 +/- 0.007 x 10 ( - 3)mm (2)/s. CONCLUSION: T2 prolongation and increased water diffusion can be balanced on DWI in C6 gliomas, resulting in isointensity on DWI (T2 shine-through washout phenomenon). ADC maps are indispensable for the correct interpretation of tumor tissue diffusion behavior.


Assuntos
Neoplasias Encefálicas/diagnóstico , Imagem de Difusão por Ressonância Magnética , Glioma/diagnóstico , Neoplasias Experimentais/diagnóstico , Animais , Progressão da Doença , Seguimentos , Modelos Lineares , Masculino , Ratos , Ratos Wistar , Fatores de Tempo
11.
Brain Pathol ; 11(2): 133-43, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11303789

RESUMO

We screened 26 ependymomas in 22 patients (7 WHO grade I, myxopapillary, myE; 6 WHO grade II, E; 13 WHO grade III, anaplastic, aE) using comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). 25 out of 26 tumors showed chromosomal imbalances on CGH analysis. The chromosomal region most frequently affected by losses of genomic material clustered on 13q (9/26). 6/7 myE showed a loss on 13q14-q31. Other chromosomes affected by genomic losses were 6q (5/26), 4q (5/26), 10 (5/26), and 2q (4/26). The most consistent chromosomal abnormality in ependymomas so far reported, is monosomy 22 or structural abnormality 22q, identified in approximately one third of Giemsa-banded cases with abnormal karyotypes. Using FISH, loss or monosomy 22q was detected in small subpopulations of tumor cells in 36% of cases. The most frequent gains involved chromosome arms 17 (8/26), 9q (7/26), 20q (7/26), and 22q (6/26). Gains on 1q were found exclusively in pediatric ependymomas (5/10). Using FISH, MYCN proto-oncogene DNA amplifications mapped to 2p23-p24 were found in 2 spinal ependymomas of adults. On average, myE demonstrated 9.14, E 5.33, and aE 1.77 gains and/or losses on different chromosomes per tumor using CGH. Thus, and quite paradoxically, in ependymomas, a high frequency of imbalanced chromosomal regions as revealed by CGH does not indicate a high WHO grade of the tumor but is more frequent in grade I tumors.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Aberrações Cromossômicas , Mapeamento Cromossômico , Ependimoma/genética , Ependimoma/patologia , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , DNA de Neoplasias/genética , Ependimoma/terapia , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico , Proto-Oncogene Mas
12.
Cancer Gene Ther ; 6(3): 254-62, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10359211

RESUMO

A new, generally applicable procedure is described for the introduction of defined costimulatory molecules into human cancer cells to increase their T-cell stimulatory capacity. The procedure involves infection with Newcastle disease virus to mediate the cell surface binding of costimulatory molecules (e.g., specially designed bispecific antibodies (bsAb)). The modification is independent of tumor cell proliferation and laborious recombinant gene technology and can be applied directly to freshly isolated and gamma-irradiated patient-derived tumor cells as an autologous cancer vaccine. Following the infection of tumor cells with a nonvirulent strain of Newcastle disease virus, the cells are washed and then further modified by coincubation with bsAbs, which attach with one arm to the viral hemagglutinin-neuraminidase (HN) molecule on the infected tumor cells. The second specificity of one bsAb (bs HN x CD28) is directed against CD28 to augment antitumor T-cell responses by selectively channeling positive costimulatory signals via the CD28 pathway. A second bsAb (bs HN x CD3) was produced to deliver T-cell receptor-mediated signals either alone (bsCD3 vaccine) or in combination with anti-CD28 (bsCD3 vaccine plus bsCD28 vaccine). In human T-cell stimulation studies in vitro, the bsCD28 vaccine caused an up-regulation of early (CD69) and late (CD25) T-cell activation markers on CD4 and CD8 T lymphocytes from either normal healthy donors or cancer patients (autologous system) and induced tumor cytostasis in nonmodified bystander tumor cells. In addition, in combination with the bsCD3 vaccine, augmented antitumor cytotoxicity and T-cell proliferative responses were observed. This tumor vaccine modification procedure is highly specific, quick, economic, and has a broad range of clinical applications.


Assuntos
Anticorpos Biespecíficos/genética , Vacinas Anticâncer , Terapia Genética/métodos , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/genética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Humanos , Hibridomas , Lectinas Tipo C , Modelos Biológicos , Receptores de Interleucina-2/genética , Linfócitos T/metabolismo , Fatores de Tempo , Células Tumorais Cultivadas
13.
Eur J Cancer ; 29A(10): 1454-61, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8398275

RESUMO

To search for a reliable proliferation marker in epithelial head and neck lesions, we have analysed the expression of the histone H3 gene by in situ hybridisation and compared this with the immunoreactivity of the widely used monoclonal antibody Ki-67. In many lesions, the Ki-67 staining failed to delineate proliferation. In contrast, the H3 hybridisation signals were in accordance with the histopathology of the biopsies: in hyperplastic epithelia, significant H3 mRNA levels were only seen in areas with inflammation. Dysplastic cells showed distinctly elevated H3 expression. Benign and semi-malignant tumours, i.e. basal cell carcinomas, showed moderate H3 signals at the periphery. In squamous cell carcinomas, H3 expression was always high at the expanding zone of the tumour and was most extensive in undifferentiated carcinomas. Thus, the expression of the histone H3 gene closely reflected the dynamics of neoplastic growth within and around head and neck tumours.


Assuntos
Neoplasias de Cabeça e Pescoço/genética , Histonas/genética , Biomarcadores Tumorais , Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/patologia , Histonas/análise , Humanos , Hibridização In Situ , Mitose , RNA Mensageiro/análise , Células Tumorais Cultivadas
14.
Semin Oncol ; 25(6): 677-96, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9865682

RESUMO

Direct infection of tumor cells with viruses transfering protective or therapeutic genes-a frequently used procedure for production of tumor vaccines in human gene therapy-is often limited by the number of tumor cells that can reliably be infected, as well as by issues of selectivity and safety. In this review, we describe an efficient, selective, and safe way of infecting human tumor cells with a natural virus with interesting pleiotropic immune stimulatory properties, the avian paramyxovirus Newcastle disease virus (NDV). Advantages of this virus are its good cell-binding properties, its selective replication in tumor cell cytoplasm, which is independent of cell proliferation, and its relative safety. Most important for its use as an adjuvant in human cancer vaccine are its ability to introduce T-cell costimulatory activity, to prevent anergy induction, and to induce locally chemokines (eg, RANTES, IP-10) and cytokines (eg, interferon alpha, beta [IFN-alpha, beta] and tumor necrosis factor-alpha [TNFalpha]) that affect T-cell recruitment and activation. A further development consists of attachment-via NDV-derived hemagluttinin-neuraminidase (HN) membrane-anchoring molecules-of universal defined bispecific reagents such as T-cell-activating anti-CD28 antibodies. Finally, we summarize the status of our clinical studies with the autologous virus modified live cell vaccine (ATV)-NDV.


Assuntos
Vacinas Anticâncer/imunologia , Imunoterapia , Vírus da Doença de Newcastle/imunologia , Animais , Anticorpos Biespecíficos/imunologia , Apresentação de Antígeno , Moléculas de Adesão Celular , Quimiocinas/biossíntese , Ensaios Clínicos como Assunto , Citocinas/biossíntese , Proteína HN/imunologia , Humanos , Ativação Linfocitária , Linfócitos T , Células Tumorais Cultivadas
15.
J Med Chem ; 44(17): 2784-92, 2001 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-11495589

RESUMO

Malignant neoplasms of the brain represent the second leading cause of cancer-related mortality in children under the age of 15. The prognosis of patients with glioblastoma multiforme, the most malignant type of gliomas, remains poor offering a median survival time of only 1 year. (2,2':6',2"-Terpyridine)platinum(II) complexes are known to possess DNA-intercalating activity and have been shown to be potential chemotherapeutic agents. In the present study we identified the selenoenzyme thioredoxin reductase (TrxR) as a major target of (2,2':6',2"-terpyridine)platinum(II) complexes. New complexes were synthesized in order to optimize this inhibition. The NADPH-reduced enzyme is inhibited almost stoichiometrically by the complexes involving a reversible competitive and an irreversible tight-binding component. For the most potent inhibitor, N,S-bis(2,2':6',2"-terpyridine)platinum(II)-thioacetimine trinitrate, the K(i) for the competitive component of the inhibition is 4 nM and the IC(50) for the tight-binding component is 2 nM after an incubation time of 5 min. The closely related but non-selenium-containing enzyme glutathione reductase is much less inhibited (by a factor of >1000). The platinum complexes were found to strongly inhibit the proliferation of three different glioblastoma cell lines as well as of two different head-and-neck squamous carcinoma cell lines. In a glioblastoma cell culture, less than 10 microM of a platinum(II) compound caused an initial drop of hTrxR activity which was followed by an increase of activity in the surviving cells. A 10 microM inhibitor added every 24 h led to 4% residual hTrxR activity but 100% glutathione reductase activity in the cells surviving for 67 h. The potential of (2,2':6',2"-terpyridine)platinum(II) complexes acting simultaneously at two different intracellular targets-hTrxR and DNA-as antitumor agents is discussed.


Assuntos
2,2'-Dipiridil/análise , 2,2'-Dipiridil/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Compostos Organoplatínicos/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , 2,2'-Dipiridil/química , Antineoplásicos/química , Divisão Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Humanos , Compostos Organoplatínicos/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
16.
Neuroscience ; 129(2): 349-60, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15501592

RESUMO

Multidrug resistance proteins (MRPs, symbol ABCC) are membrane glycoproteins that mediate the ATP-dependent export of organic anions, including cytotoxic and antiviral drugs, from cells. To identify MRP family members possibly involved in the intrinsic resistance of human brain to cytotoxic and antiviral drugs, we analyzed the expression and localization of MRP1-MRP6 in rapidly frozen perilesional samples of several regions of adult human brain obtained during neurosurgery. Quantitative polymerase chain reaction analysis showed expression of MRP1, MRP2, MRP3, MRP4, and MRP5 mRNA, whereas MRP6 mRNA was below detectability. However, immunofluorescence microscopy of cryosections from human brain showed no reactivity for the MRP2 or MRP3 proteins. The proteins MRP1, MRP4, and MRP5 were clearly localized by confocal laser scanning microscopy to the luminal side of brain capillary endothelial cells. The MRP4 and MRP5 proteins were also detected in astrocytes of the subcortical white matter. Notably, MRP5 protein was present in pyramidal neurons. MRP proteins may, thus, contribute to the cellular efflux of endogenous anionic glutathione or glucuronate conjugates (substrates for MRP1), cyclic nucleotides (substrates for MRP4 and MRP5), or glutathione (co-substrate for MRP1 and MRP4); in addition, they may play an important role in the resistance of the brain to several cytotoxic and antiviral drugs.


Assuntos
Transportadores de Cassetes de Ligação de ATP/biossíntese , Química Encefálica/fisiologia , Genes MDR/genética , Astrócitos/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/cirurgia , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Hemorragia Cerebral/metabolismo , Glioma/metabolismo , Glioma/cirurgia , Humanos , Imuno-Histoquímica , Microscopia de Fluorescência , Células Piramidais/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Versicherungsmedizin ; 50(5): 173-9, 1998 Oct 01.
Artigo em Alemão | MEDLINE | ID: mdl-9816989

RESUMO

Although the frequency of primary brain tumors is relatively small compared to other tumors such as breast or lung carcinoma, brain tumors affect a particularly young and healthy patient population and possess a high portion of cancer mortality in these age groups. Generally brain tumor diseases influence the professional capacity in younger people and cause significant socioeconomical costs. Prognosis and clinical deterioration of primary brain tumors are determined by histopathological diagnosis first, by tumor location and -volume second. The clinical malignancy of brain tumors, caused by histopathological findings, has not essentially been changed in the last years despite more effective therapies. In contrast refinement in technical standards and computer-assisted micro-surgery makes a valuable progress in the treatment of biological benign brain tumors. Most of these patients recover normal efficiency including former working capability. On the other hand therapeutical nihilism is not supposed to be a sufficient answer to primary brain tumors, because in selected cases a longer lasting stabilization of the disease is possible. In future only through better understanding of the biology of brain tumors and much more effective therapies we can hope to make significant progress in the treatment of these tumors.


Assuntos
Astrocitoma/mortalidade , Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , Neoplasias Meníngeas/mortalidade , Meningioma/mortalidade , Astrocitoma/diagnóstico , Astrocitoma/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Feminino , Alemanha/epidemiologia , Glioblastoma/diagnóstico , Glioblastoma/terapia , Humanos , Masculino , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/terapia , Meningioma/diagnóstico , Meningioma/terapia , Prognóstico , Taxa de Sobrevida
18.
Cell Death Differ ; 21(6): 929-40, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24531536

RESUMO

Glioblastomas are highly aggressive brain tumours and are characterised by substantial cellular heterogeneity within a single tumour. A sub-population of glioblastoma stem-like cells (GSCs) that shares properties with neural precursor cells has been described, exhibiting resistance to therapy and therefore being considered responsible for the high recurrence rate in glioblastoma. To elucidate the underlying cellular processes we investigated the role of phosphatases in the GSC phenotype, using an in vitro phosphatome-wide RNA interference screen. We identified a set of genes, the knockdown of which induces a significant decrease in the glioma stem cell marker CD133, indicating a role in the glioblastoma stem-like phenotype. Among these genes, the ecto-nucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) was found to be highly expressed in GSCs compared with normal brain and neural stem cells. Knockdown of ENPP1 in cultured GSCs resulted in an overall downregulation of stem cell-associated genes, induction of differentiation into astrocytic cell lineage, impairment of sphere formation, in addition to increased cell death, accumulation of cells in G1/G0 cell cycle phase and sensitisation to chemotherapeutic treatment. Genome-wide gene expression analysis and nucleoside and nucleotide profiling revealed that knockdown of ENPP1 affects purine and pyrimidine metabolism, suggesting a link between ENPP1 expression and a balanced nucleoside-nucleotide pool in GSCs. The phenotypic changes in E-NPP1-deficient GSCs are assumed to be a consequence of decreased transcriptional function of E2F1. Together, these results reveal that E-NPP1, by acting upstream of E2F1, is indispensable for the maintenance of GSCs in vitro and hence required to keep GSCs in an undifferentiated, proliferative state.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Células-Tronco Neurais/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Pirofosfatases/metabolismo , Antígeno AC133 , Antígenos CD/biossíntese , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Pontos de Checagem do Ciclo Celular/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Linhagem da Célula , Fator de Transcrição E2F1/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/patologia , Glicoproteínas/biossíntese , Humanos , Peptídeos , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética
19.
Oncogene ; 31(44): 4698-708, 2012 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-22249262

RESUMO

The Notch1-mediated signaling pathway has a central role in the maintenance of neural stem cells and contributes to growth and progression of glioblastomas, the most frequent malignant brain tumors in adults. Here, we demonstrate that the Notch1 receptor promotes survival of glioblastoma cells by regulation of the anti-apoptotic Mcl-1 protein. Notch1-dependent regulation of Mcl-1 occurs cell type dependent at a transcriptional or post-translational level and is mediated by the induction of epidermal growth factor receptor (EGFR). Inhibition of the Notch1 pathway overcomes apoptosis resistance and sensitizes glioblastoma cells to apoptosis induced by ionizing radiation, the death ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or the Bcl-2/Bcl-XL inhibitor ABT-737. In conclusion, targeting Notch1 might represent a promising novel strategy in the treatment of glioblastomas.


Assuntos
Receptores ErbB/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptor Notch1/metabolismo , Transdução de Sinais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas Proto-Oncogênicas c-raf/metabolismo , Processamento Pós-Transcricional do RNA , Receptor Notch1/genética , Transcrição Gênica
20.
Oncogene ; 31(49): 5108-16, 2012 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-22286769

RESUMO

Aberrant promoter methylation of different DNA repair genes has a critical role in the development and progression of various cancer types, including head and neck squamous cell carcinomas (HNSCCs). A systematic analysis of known human repair genes for promoter methylation is however missing. We generated quantitative promoter methylation profiles in single CpG units of 160 human DNA repair genes in a set of DNAs isolated from fresh frozen HNSCC and normal tissues using MassARRAY technology. Ninety-eight percent of these genes contained CpG islands (CGIs) in their promoter region; thus, DNA methylation is a potential regulatory mechanism. Methylation data were obtained for 145 genes, from which 15 genes exhibited more than a 20% difference in methylation levels between tumor and normal tissues, manifested either as hypermethylation or as hypomethylation. Analyses of promoter methylation with mRNA expression identified the DNA glycosylase NEIL1 (nei endonuclease VIII-like 1) as the most prominent candidate gene. NEIL1 promoter hypermethylation was confirmed in additional fresh frozen HNSCC samples, normal mucosa, HNSCC cell lines and primary human skin keratinocytes. The investigation of laser-microdissected tissues further substantiated increased methylation levels in tumor versus matched non-tumor cells. Immunohistological analysis revealed significantly less NEIL1 protein expression in tumor tissues. 5-Aza-2'-deoxycytidine treatment and DNMT1 knockdown resulted in the re-expression of NEIL1 in HNSCC cell lines, which initially carried hypermethylated promoter regions. In conclusion, our results suggest that DNA methylation contributes to the downregulation of NEIL1 expression and might thus have a role in modulating the response to therapies of HNSCC.


Assuntos
Carcinoma de Células Escamosas/genética , DNA Glicosilases/genética , Metilação de DNA , Reparo do DNA/genética , Neoplasias de Cabeça e Pescoço/genética , Regiões Promotoras Genéticas , Idoso , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Linhagem Celular Tumoral/efeitos dos fármacos , Ilhas de CpG , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA Glicosilases/metabolismo , Decitabina , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Queratinócitos/fisiologia , Masculino , Pessoa de Meia-Idade , Valores de Referência , Carcinoma de Células Escamosas de Cabeça e Pescoço
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