RESUMO
Among gliomas types, glioblastoma is considered the most malignant and the worst form of primary brain tumor. It is characterized by high infiltration rate and great angiogenic capacity. The presence of an inflammatory microenvironment contributes to chemo/radioresistance, resulting in poor prognosis for patients. Recent data show that thiazolidinones have a wide range of pharmacological properties, including anti-inflammatory and antiglioma activities. Nanocapsules of biodegradable polymers become an alternative to cancer treatment since they provide targeted drug delivery and could overcome blood-brain barrier. Therefore, here we investigated the in vitro antiglioma activity and the potential in vivo toxicity of 2- (2-methoxyphenyl) -3- ((piperidin-1-yl) ethyl) thiazolidin-4-one-loaded polymeric nanocapsules (4L-N). Nanocapsules were prepared and characterized in terms of particle size, polydispersity index, zeta potential, pH, molecule content and encapsulation efficiency. Treatment with 4L-N selectively decreased human U138MG and rat C6 cell lines viability and proliferation, being even more efficient than the free-form molecule (4L). In addition, 4L-N did not promote toxicity to primary astrocytes. We further demonstrated that the treatment with sub-therapeutic dose of 4L-N did not alter weight, neither resulted in mortality, toxicity or peripheral damage to Wistar rats. Finally, 4L as well as 4L-N did not alter makers of oxidative damage, such as TBARS levels and total sulfhydryl content, and did not change antioxidant enzymes SOD and CAT activity in liver and brain of treated rats. Taken together, these data indicate that the nanoencapsulation of 4L has potentiated its antiglioma effect and does not cause in vivo toxicity.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Nanocápsulas/química , Piperidinas/toxicidade , Piperidinas/uso terapêutico , Polímeros/química , Tiazolidinas/toxicidade , Tiazolidinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Biomarcadores Tumorais/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Glioma/sangue , Glioma/patologia , Humanos , Luz , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/química , Polímeros/síntese química , Ratos Wistar , Tiazolidinas/síntese química , Tiazolidinas/química , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Testes de Toxicidade , Redução de Peso/efeitos dos fármacosRESUMO
BACKGROUND: Pediatric neuroectodermal malignancies express N-glycolylated gangliosides including N-glycolyl GM3 (NeuGcGM3) as targets for immunotherapy. PROCEDURE: We evaluated the toxicity and maximum tolerated dose and immunological response of racotumomab, an anti-idiotype vaccine targeting NeuGcGM3 through a Phase I study enrolling children with relapsed or resistant tumors expressing NeuGcGM3. MATERIALS AND METHODS: Drug dose was escalated to three levels (0.15-0.25-0.4 mg) of racotumomab administered intradermally. Each drug level included three patients receiving a total of three doses, every 14 days. A confirmation cohort was added to the highest dose level. Antibody response was assessed upon study entry and at 4-week intervals for at least three immunological determinations for each patient. RESULTS: Fourteen patients were enrolled (10 with neuroblastoma, one with retinoblastoma, one with Wilms' tumor, and two with brainstem glioma). Three patients completed the three drug levels and three were enrolled in the confirmation cohort. One patient died of tumor progression before completing the three applications. Racotumomab was well tolerated. The only side effect observed was grade 1-2 toxicity at the injection site. Racotumomab elicited an IgM and/or IgG antibody response directed against NGcGM3 in nine patients and IgM against racotumomab in 11 of 13 evaluable patients. The maximum tolerated dose was not reached and no dose-limiting toxicity was seen. CONCLUSIONS: Racotumomab vaccination has a favorable toxicity profile up to a dose of 0.4 mg, and most patients elicited an immune response. Its activity as immunotherapy for neuroectodermal malignancies will be tested in further clinical trials.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Neoplasias do Tronco Encefálico/tratamento farmacológico , Vacinas Anticâncer/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioma/tratamento farmacológico , Neuroblastoma/dietoterapia , Tumor de Wilms/tratamento farmacológico , Anticorpos Monoclonais Murinos , Anticorpos Antineoplásicos/sangue , Neoplasias do Tronco Encefálico/sangue , Criança , Pré-Escolar , Feminino , Gangliosídeos/biossíntese , Regulação Neoplásica da Expressão Gênica , Glioma/sangue , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Lactente , Masculino , Neuroblastoma/sangue , Vacinação , Tumor de Wilms/sangueRESUMO
Introdução e objetivos: O glioblastoma multiforme é um glioma de alto grau que apresenta um prognóstico ruim. O diagnóstico definitivo é estabelecido pela avaliação histológica, porém este pode apresentar conflitos na classificação, com isso surge à necessidade de ferramentas que auxiliem o patologista em sua análise. Atualmente, maior ênfase tem sido dada a alterações na glicosilação, pois estão associadas a neoplasias, e a descoberta da capacidade de lectinas em reconhecer tais alterações fez destas, ferramentas aplicáveis para o diagnóstico biomédico. Dessa forma, o objetivo deste trabalho é analisar a marcação das lectinas CpL, WGA e Con A em células da linhagem C6...
Introduction and objectives: Glioblastoma multiforme is a high-grade glioma that has a poor prognosis. The definitive diagnosis is established by histological assessment. However, this can present conflicts in grading gliomas, which justifies new tools to assist the pathologist in his analysis. Currently, it is known that there are changes in glycosylation pattern of molecules associated with cancer, and the discovery of the ability of lectins to recognize these changes made these tools applicable for biomedical diagnosis. Thus, the aim of this study is to analyze the labelling of C6...
Assuntos
Humanos , Glioma/complicações , Glioma/diagnóstico , Glioma/imunologia , Glioma/patologia , Glioma/sangue , Lectinas , Lectinas/análise , Lectinas/fisiologia , Lectinas/imunologiaRESUMO
Hypomethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter in glioma cells has been associated with temozolomide resistance. S-adenosylmethionine (SAM), which is produced during folate metabolism, is the main source of methyl groups during DNA methylation. As a key enzyme during folate metabolism, polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) may regulate folate end-products. We investigated the effect of typical polymorphisms of MTHFR (C677T and A1298C) on MGMT methylation based on different serum folate levels in patients with glioma from Northeast China. A total of 275 patients with glioma and 329 without malignant tumors were tested. Serum folate concentration was assayed by using the electrochemiluminescence immunoassay. MTHFR polymorphisms were detected by Taqman-Fluorescence quantitative polymerase chain reaction (PCR). Methylation-specific PCR was used to assess MGMT methylation. The constituent ratio of glioma patients below the serum folate biological reference value was significantly higher than that of the control population (P < 0.001). In patients with oligodendroglioma and glioblastoma, heterozygotes for the A1298C mutation were found in higher frequency than homozygotes or wild types (oligodendroglioma, P < 0.001; glioblastoma, P < 0.01). When grouped by the median or biological reference value of serum folate, only homozygotes for C677T with low levels of folate were significantly associated with decreased methylation of MGMT (median, P < 0.001; biological reference value, P = 0.036). These data suggest that, in combination with a negative folate balance in glioma patients, T/T genotypes in MTHFR C677T may be associated with MGMT demethylation.
Assuntos
Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Ácido Fólico/sangue , Glioma/sangue , Glioma/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Proteínas Supressoras de Tumor/genética , Adulto , Alelos , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras GenéticasRESUMO
PURPOSE: Malignant gliomas are associated with alteration in EGF/EGFR signaling. Functional EGF+61A>G polymorphism is implicated with risk, recurrence, and progression of glioma. This study aimed to establish a putative association of EGF+61A>G with risk of glioma development, production of angiogenic growth factor EGF, and the response to perillyl alcohol administered by intranasal route. METHODS: The study included 83 patients with recurrent glioma enrolled in Phase I/II trial for intranasal perillyl alcohol therapy and subjects without cancer (n = 196) as control group. DNA was extracted from blood samples, EGF genotype performed with PCR-RFLP assay, and EGF circulating levels by enzyme immunoassay. Adequate statistical tests were performed to verify associations between polymorphism and glioma risk, and genotype correlation with EGF circulating levels. The log-rank test was also used to evaluate differences on patient survival. RESULTS: Patients with primary glioblastoma had high frequency of AA genotype (p = 0.037) and A allele (p = 0.037). Increased EGF circulating levels were observed in glioma patients with AA (p = 0.042), AG (p = 0.006), and AA + AG (p = 0.008) genotypes compared with GG. Patients with GG genotype showed increased but not significant (p > 0.05) survival rate, and EGF levels lower than 250 pg/mL was consistently (p = 0.0374) associated with increased survival. CONCLUSION: Presence of EGF+61A>G polymorphism in Brazilian subjects was associated with glioma risk and increased circulating EGF levels. Better response to perillyl alcohol-based therapy was observed in a group of adult Brazilian subjects with lower EGF levels.
Assuntos
Neoplasias Encefálicas/genética , Fator de Crescimento Epidérmico/genética , Glioma/genética , Monoterpenos/uso terapêutico , Polimorfismo de Nucleotídeo Único , Administração Intranasal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/tratamento farmacológico , Brasil , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Fator de Crescimento Epidérmico/sangue , Feminino , Frequência do Gene , Genótipo , Glioma/sangue , Glioma/tratamento farmacológico , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Monoterpenos/administração & dosagem , Estudos Prospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Gliomas of astrocytic origin are the most common primary brain tumors, accounting for over 40 to 50 of all central nervous system tumors. The TP53 tumor suppressor gene is the most frequently mutated gene found in human malignancies. A mutation of this gene can lead to an increased half-life of the resulting protein and loss of biological function. High levels of p53 have been detected in the serum of colon cancer patients, although p53 protein has not been detected in the serum of brain tumor patients. Besides circulating p53, several studies have detected antibodies against p53 in patients with lung and breast cancer, as well as those with other types of cancer. We studied p53 protein and anti-p53 antibodies in the plasma of Brazilian brain tumor patients. Plasma samples were drawn from 24 untreated brain tumor patients and from 15 healthy donors without clinical signs of cancer. Western blotting techniques were used to detect p53 protein and anti-p53 antibodies. We found anti-p53 antibodies in 5/24 brain tumor patients. Age appears to affect the immune response, as four of six tumor patients under 16 years old had detectable anti-p53 antibodies, while these were found in only 1 of 18 adults (over 16 years old). We found no p53 protein in any of the serum samples from the brain tumors. Possibly the presence of this protein is affected by tumor type or by the organs that are sampled
Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Anticorpos Antineoplásicos/sangue , /imunologia , Glioma/imunologia , Neoplasias Encefálicas/imunologia , Proteína Supressora de Tumor p53 , Western Blotting , Brasil , /genética , Glioma/sangue , Glioma/genética , Mutação , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/genética , Proteínas Recombinantes/sangue , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteína Supressora de Tumor p53RESUMO
Gliomas of astrocytic origin are the most common primary brain tumors, accounting for over 40 to 50% of all central nervous system tumors. The TP53 tumor suppressor gene is the most frequently mutated gene found in human malignancies. A mutation of this gene can lead to an increased half-life of the resulting protein and loss of biological function. High levels of p53 have been detected in the serum of colon cancer patients, although p53 protein has not been detected in the serum of brain tumor patients. Besides circulating p53, several studies have detected antibodies against p53 in patients with lung and breast cancer, as well as those with other types of cancer. We studied p53 protein and anti-p53 antibodies in the plasma of Brazilian brain tumor patients. Plasma samples were drawn from 24 untreated brain tumor patients and from 15 healthy donors without clinical signs of cancer. Western blotting techniques were used to detect p53 protein and anti-p53 antibodies. We found anti-p53 antibodies in 5/24 brain tumor patients. Age appears to affect the immune response, as four of six tumor patients under 16 years old had detectable anti-p53 antibodies, while these were found in only 1 of 18 adults (over 16 years old). We found no p53 protein in any of the serum samples from the brain tumors. Possibly the presence of this protein is affected by tumor type or by the organs that are sampled.