RESUMO
The vast majority of mesenchymal tumors originating from the GI tract consists of gastrointestinal stromal tumors (GIST), an entity just recently defined. The incidence is estimated to be around 10 - 20/1000000, the median age at diagnosis has been reported to be 55 to 65 years. GISTs most commonly occur in the stomach or duodenum, followed by the small intestine. About half of the patients present with metastatic disease at first diagnosis, predominantly in the liver or periteneum. GISTs are strongly and uniformly positive for CD117 (c-kit), a type III receptor-tyrosine kinase. Kit mutations, mostly in exon 11, leading to ligand independent constitutive activation are supposed to play a major role in the pathogenesis of GIST. Until recently no active systemic treatment was available for advanced gastrointestinal stromal tumors. Imatinib (STI571 = Glivec) is a rationally designed, orally available phenylaminopyrimidin analogue. The mechanism of action consists of a competitive interaction with the ATP-binding pocket of specific tyrosine kinases. Early results from clinical trials with response rates around 60 % and progression arrest in more than 80 % of patients resulting in fast relief of symptoms, confirm the high activity of this novel treatment. The role of adjuvant treatment after potentially curative resection of GIST is currently evaluated in ongoing clinical trials. Patients with progressive disease while under treatment with Imatinib should be enrolled in studies testing novel treatment strategies as RAD001, PKC412 or SU11 248.
Assuntos
Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/terapia , Administração dos Cuidados ao Paciente/métodos , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Células Estromais/patologia , Antineoplásicos/uso terapêutico , Benzamidas , Quimioterapia Adjuvante/métodos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/cirurgia , Humanos , Mesilato de Imatinib , Padrões de Prática Médica , Proteínas Proto-Oncogênicas c-kit/sangue , Proteínas Proto-Oncogênicas c-kit/genéticaRESUMO
Gastric cancer is highly refractory to DNA-damaging therapies. We therefore studied both gene mutation and protein expression of p53 and Bax in a cohort of 116 patients with gastric cancer who underwent R0-resection with a curative intent. Bax mutation was independent from severe microsatellite instability (MSI), that is, global mismatch repair deficiency as determined by analysis of BAT-25/BAT-26 microsatellite markers. Thus, Bax-frameshift mutation is a feature of tumors with low MSI. In contrast and as expected, no p53 mutations were observed in the microsatellite instable tumors. p53 Mutation or p53 overexpression did not have an impact on disease prognosis. p53-Inactivation was, however, associated with an extremely poor prognosis in the subgroup of patients with Bax-mutated tumors. Thus, we show for the first time that the combined mutation of p53 and Bax, two key regulators of the mitochondrial apoptosis pathway, results in an extremely aggressive tumor biology and poor clinical prognosis.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma/genética , Repetições de Microssatélites/genética , Mutação/genética , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas/genética , Neoplasias Gástricas/genética , Proteína Supressora de Tumor p53/genética , Apoptose/genética , Carcinoma/diagnóstico , Carcinoma/mortalidade , Transformação Celular Neoplásica/genética , Estudos de Coortes , Reparo do DNA/genética , Humanos , Prognóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida , Proteína X Associada a bcl-2Assuntos
Afinidade de Anticorpos , Adesão Celular/imunologia , Endotélio Vascular/imunologia , Peróxido de Hidrogênio/farmacologia , Integrinas/imunologia , Células Matadoras Naturais/imunologia , Receptores Fc/fisiologia , Animais , Oxirredução , Receptores Fc/efeitos dos fármacos , Valores de Referência , SuínosRESUMO
The purpose of our study was to determine the expression of the pro-apoptotic BAX protein in relation to the mutational status of BAX and p53 (as transcriptional activator of the BAX gene) in benign and malignant thyroid tissue. In 47 patients with thyroid tumours (14 follicular and 3 papillary carcinomas, 14 adenomas and 16 goitres), the DNA was screened for mutations of BAX (exon 1-6) and p53 (exon 5-8) by single-strand conformation polymorphism polymerase chain reaction (SSCP-PCR). Furthermore, the protein expression of BAX, p53 and p21 (which is also increased transcriptionally by p53) was investigated by immunohistochemistry. Surprisingly, we observed elevated BAX levels in patients with thyroid carcinomas compared with patients with adenomas (unpaired t-test: p<0.05) or with goitres (p<0.02). This is in clear contrast to other carcinomas where BAX is frequently inactivated which correlates to a poor prognosis (Sturm et al. J. Clin. Oncol. 1999;17:1364-74.). There were no significant differences of the BAX levels between goitres or the adenomas. In the SSCP-PCR analysis, no BAX mutations were detectable. P53 mutation analysis by SSCP-PCR did not reveal any functional p53 mutations in the patients with carcinomas, adenomas or goitres. Nevertheless, patients with carcinomas showed an overexpression (preferentially cytoplasmic) of p53 protein compared with patients with benign tumours (p<0.05). The absence of p53 mutations suggests that the overexpressed p53 is wild type. This is in line with the expression profile of BAX and p21, which showed a higher protein expression in these p53 positive tumours (p<0.05 in the carcinomas compared with the non-malignant lesions). Consequently, the overexpressed p53 might be a correlate for dysregulation without loss of function. This, in turn, might be a reason for the good outcome of some patients with thyroid cancer.
Assuntos
Carcinoma/metabolismo , Genes p53/genética , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas p21(ras)/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Neoplasias da Glândula Tireoide/metabolismo , Proteína Supressora de Tumor p53/biossíntese , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/metabolismo , Adenoma/genética , Adenoma/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Carcinoma/genética , Carcinoma Papilar/genética , Carcinoma Papilar/metabolismo , Citoplasma/metabolismo , Análise Mutacional de DNA , Éxons , Feminino , Bócio/genética , Bócio/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Conformacional de Fita Simples , Neoplasias da Glândula Tireoide/genética , Transcrição Gênica , Ativação Transcricional , Resultado do Tratamento , Proteína X Associada a bcl-2RESUMO
Synthesis and antiparasitic activity vs T. cruzi and L. donovani of a series of 9-thioaryl acridines are reported. A convenient correlation between molecular structure and biological activity is proposed. Results not only agree with the classical interactions of acridines with DNA but also suggest possible role of charge transfer complexes.
Assuntos
Tripanossomicidas/síntese química , Trypanosoma/efeitos dos fármacos , Acridinas/síntese química , Acridinas/farmacologia , Animais , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Relação Quantitativa Estrutura-Atividade , Tripanossomicidas/farmacologiaRESUMO
BACKGROUND: The unique mechanism of dithizone action in the interior of the viable pancreatic islet suggests the possible development of a specific radiopharmaceutical that may have a potential clinical application in the diagnosis of the pancreatic organ allografts or islets rejection. The radiodiagnostic properties of the newly developed radioactive analogue of dithizone, i.e. Dithizone-[(131)I]-Histamine conjugate have been evaluated in the present study. METHODS: The four islet cells transplantation models were chosen for this purpose. The most important feature of the Dithizone-[(131)I]-Histamine conjugate is its possessed ability of zinc chelation. As was presented in the recent study, the conjugate stains pink-reddish the isolated pancreatic islets in vitro. Among the studied transplantation models, only the islets grafting under testis capsule enabled determination of the pancreatic islets in rats by radioactive Dithizone-[(131)I]-Histamine conjugate. The level of the radioactivity in the recipient testis (right) was almost two times higher compared to the controls (0.24 vs. 0.13% ID/g, respectively). CONCLUSIONS: These preliminary data demonstrate the ability of the developed radioactive analogue of dithizone for in vivo identification of transplanted pancreatic islets, and suggests a potential clinical application of the radiodithizone in the diagnosis of the pancreatic islet rejection.
RESUMO
Synthesis and activity, vs. leukaemia cells of new 9-thiadiazolo acridine derivatives are reported. In addition, electronic properties and molecular structure are correlated with biological activity of these molecules. Results are in agreement with the capability of drugs to intercalate into DNA.
Assuntos
Acridinas/farmacologia , Antineoplásicos/farmacologia , Tiadiazóis/farmacologia , Animais , Leucemia L1210/tratamento farmacológico , Leucemia L1210/patologia , Camundongos , Relação Quantitativa Estrutura-AtividadeRESUMO
The circadian heart rate course was assessed in 3 groups of patients with left ventricular ejection fraction (LVEF) 10-15%, 20-25% and 30-35%. The study comprised 36 persons. In 9 patients heart failure was due to MI and in 17--to dilated cardiomyopathy. Those with atrial fibrillation, ventricular tachycardia, supraventricular tachycardia, diabetes, valvular heart diseases and with central system disorders were excluded from the study. Left ventricular ejection fraction was evaluated by echocardiography. Heart rate, calculated as a mean value every 5 minutes, was taken in patients during 24 hour recordings. For each patient separately, mean value of all measurement was calculated. Then a ratio of each actual value to the mean value was calculated. This ratio was defined as relative heart rate; [formula: see text] Circadian heart rate courses were approximated by Fourier row: [formula: see text]. The 24 harmonics were analyzed. Statistically significant differences in circadian courses were closed to amplitudes of 1st, 12th, 13th, 14th, 16th, 18th harmonics. Using test of variance homogeneity it has been demonstrated that variability of amplitudes of 12th and 17th harmonics as well as phase of 5th harmonic depend on left ventricular ejection fraction.