RESUMO
PURPOSE: Greater scrutiny is being placed on developing a full understanding of potential cardiotoxicity of therapeutic agents, especially on the potential to prolong the QTc interval which can lead to arrhythmias such as torsade de pointes and sudden death. This trial was designed to specifically evaluate the effect, if any, of cetuximab on the QTc interval in patients with advanced solid tumors. METHODS: Cetuximab was administered as an initial dose of 400 mg/m(2) on day 1 (week 1) followed by a maintenance dose of 250 mg/m(2) weekly thereafter. ECG monitoring was performed at screening, baseline (week 1 preceding dosing), and during week 1 to 5 of treatment. Cetuximab concentration-to-QTc relationship was evaluated based on cetuximab serum samples obtained at the time of each ECG measurement to allow for accurate correlation between any observed QT/QTc changes and cetuximab serum concentration. RESULTS: At the recommended dose (400 mg/m(2) on day 1 followed by 250 mg/m(2) weekly), cetuximab had no clinically meaningful effect on QTc interval, PR or QRS intervals, or heart rate and there was no apparent concentration-dependent effect of cetuximab on any of these electrocardiogram parameters. Safety observations in patients treated with cetuximab in this study were consistent with the agent's known safety profile. CONCLUSION: These results suggest that cetuximab can be safely administered as a single agent without risk of effect on QTc interval.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Coração/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Cetuximab , Interpretação Estatística de Dados , Relação Dose-Resposta a Droga , Esquema de Medicação , Eletrocardiografia Ambulatorial , Feminino , Humanos , Infusões Intravenosas , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/patologia , Resultado do Tratamento , Estados UnidosRESUMO
Cyclooxygenase (COX)-2 and the prostaglandins resulting from its enzymatic activity have been shown to play a role in modulating cell growth and development of human neoplasia. Evidence includes a direct relationship between COX-2 expression and cancer incidence in humans and animal models, increased tumorigenesis after genetic manipulation of COX-2, and significant anti-tumor properties of non-steroidal anti-inflammatory drugs in animal models and in some human cancers. Recent data showed that COX-2 and the derived prostaglandins are involved in control of cellular growth, apoptosis, and signal through a group of nuclear receptors named peroxisome proliferator-activated receptors (PPARs). In this article we will review some of the findings suggesting that COX-2 is involved in multiple cellular mechanisms that lead to tumorigenesis.
Assuntos
Divisão Celular/fisiologia , Transformação Celular Neoplásica , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Antineoplásicos/metabolismo , Apoptose/fisiologia , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/metabolismo , Regulação Enzimológica da Expressão Gênica , Humanos , Isoenzimas/genética , Proteínas de Membrana , Prostaglandina-Endoperóxido Sintases/genética , Prostaglandinas/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismoRESUMO
The cyclooxygenase (COX)-2 gene encodes an inducible prostaglandin synthase enzyme that is overexpressed in adenocarcinomas and other tumors. Deletion of the murine Cox-2 gene in Min mice reduced the incidence of intestinal tumors, suggesting that it is required for tumorigenesis. However, it is not known if overexpression of Cox-2 is sufficient to induce tumorigenic transformation. We have derived transgenic mice that overexpress the human COX-2 gene in the mammary glands using the murine mammary tumor virus promoter. The human Cox-2 mRNA and protein are expressed in mammary glands of female transgenic mice and were strongly induced during pregnancy and lactation. Female virgin Cox-2 transgenic mice showed precocious lobuloalveolar differentiation and enhanced expression of the beta-casein gene, which was inhibited by the Cox inhibitor indomethacin. Mammary gland involution was delayed in Cox-2 transgenic mice with a decrease in apoptotic index of mammary epithelial cells. Multiparous but not virgin females exhibited a greatly exaggerated incidence of focal mammary gland hyperplasia, dysplasia, and transformation into metastatic tumors. Cox-2-induced tumor tissue expressed reduced levels of the proapoptotic proteins Bax and Bcl-x(L) and an increase in the anti-apoptotic protein Bcl-2, suggesting that decreased apoptosis of mammary epithelial cells contributes to tumorigenesis. These data indicate that enhanced Cox-2 expression is sufficient to induce mammary gland tumorigenesis. Therefore, inhibition of Cox-2 may represent a mechanism-based chemopreventive approach for carcinogenesis.
Assuntos
Isoenzimas/genética , Neoplasias Mamárias Experimentais/etiologia , Neoplasias Mamárias Experimentais/genética , Prostaglandina-Endoperóxido Sintases/genética , Animais , Ciclo-Oxigenase 2 , Feminino , Regulação Enzimológica da Expressão Gênica , Isoenzimas/biossíntese , Neoplasias Mamárias Experimentais/enzimologia , Camundongos , Camundongos Transgênicos , Prostaglandina-Endoperóxido Sintases/biossínteseRESUMO
Overexpression of the cyclooxygenase-2 (COX-2) gene is observed in several neoplastic diseases. However, molecular mechanisms involved in the regulation of expression of COX-2 are not well understood. In this report, we describe a unique post-transcriptional regulatory mechanism of COX-2 mRNA stabilization in MDA-MB-231 cells, a highly metastatic cell line derived from a human mammary tumor. High levels of COX-2 mRNA, protein, and enzyme activity were induced by serum withdrawal, which were potently inhibited by the addition of serum or >100-kDa serum factor. Nuclear run-on analysis and actinomycin D chase experiments indicate that regulation is primarily at the level of post-transcriptional mRNA stability. Interestingly, SB203580, an inhibitor of the p38 stress-activated protein kinase (SAPK), and overexpression of the dominant-negative p38alpha construct potently inhibited the serum withdrawal-induced COX-2 mRNA levels. Indeed, the half-life of COX-2 mRNA decreased from 9 to 4.5 h after SB203580 treatment, suggesting that signal transduction by the p38 SAPK pathway is required for COX-2 mRNA stability.
Assuntos
Neoplasias da Mama/metabolismo , Isoenzimas/metabolismo , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Processamento Pós-Transcricional do RNA , RNA Mensageiro/metabolismo , Apoptose , Northern Blotting , Western Blotting , Bromodesoxiuridina/metabolismo , Ciclo Celular , Núcleo Celular/metabolismo , Meios de Cultura Livres de Soro/metabolismo , Ciclo-Oxigenase 2 , Dactinomicina/farmacologia , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica , Genes Dominantes , Humanos , Imidazóis/farmacologia , Proteínas de Membrana , Microscopia de Fluorescência , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Inibidores da Síntese de Ácido Nucleico/farmacologia , Piridinas/farmacologia , Transdução de Sinais , Fatores de Tempo , Transfecção , Células Tumorais Cultivadas , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
The immediate-early gene cyclooxygenase 2 (Cox-2) is induced in a variety of hyperplastic pathological conditions, including rheumatoid arthritis and colorectal cancer. Although a causal role for Cox-2 has been proposed, mechanisms by which Cox-2 function contributes to the pathogenesis of hyperplastic disease are not well defined. We constructed a green fluorescent protein-tagged Cox-2 (Cox-2-GFP) to examine its effects on a variety of cell types upon overexpression. Subcellular localization and enzymatic and pharmacological properties of Cox-2-GFP polypeptide were indistinguishable from those of the wild-type Cox-2 polypeptide. Overexpression of the Cox-2-GFP or the Cox-2 polypeptide by transient transfection suppressed the population of cells in the S phase of the cell cycle, with a concomitant increase in G(0)/G(1) population. In contrast, transient overexpression of GFP had no effect on cell cycle distribution, whereas endoplasmic reticulum-retained GFP (GFP-KDEL) overexpression was associated with only a minor decrease of cells in S phase. Interestingly, neither NS-398 (a Cox-2-specific inhibitor) nor indomethacin could reverse the effect of Cox-2-GFP overexpression on cell cycle progression. Furthermore, two mutants of Cox-2, S516Q and S516M, which lack the cyclooxygenase activity, exhibited the same effect as Cox-2-GFP. The cell cycle effect of Cox-2-GFP was observed in ECV-304, NIH 3T3, COS-7, bovine microvascular endothelial cells, and human embryonic kidney 293 cells. These findings suggest that Cox-2 inhibits cell cycle progression in a variety of cell types by a novel mechanism that does not require the synthesis of prostaglandins.
Assuntos
Ciclo Celular/fisiologia , Isoenzimas/genética , Prostaglandina-Endoperóxido Sintases/genética , Células 3T3 , Animais , Células COS , Ciclo Celular/genética , Linhagem Celular , Ciclo-Oxigenase 2 , Fase G1/genética , Fase G1/fisiologia , Regulação Enzimológica da Expressão Gênica , Proteínas de Fluorescência Verde , Humanos , Isoenzimas/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Proteínas de Membrana , Camundongos , Microscopia de Fluorescência , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas/fisiologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Fase de Repouso do Ciclo Celular/genética , Fase de Repouso do Ciclo Celular/fisiologia , TransfecçãoRESUMO
The cyclooxygenase isoenzymes (COX-1 and -2) catalyze the rate-limiting steps in prostanoid biosynthesis. COX-1 and -2 genes encode two isoenzymes with overlapping yet distinct expression patterns and functions. Physiologically, various extracellular stimuli such as growth factors, cytokines and tumor promoters regulate the expression of COX-1 and -2 genes at both transcriptional and post-transcriptional levels. COX-2 is overexpressed in rheumatoid arthritis, colorectal and breast cancer. Prostanoids produced by the COX pathway signal via plasma membrane-localized, G-protein-coupled receptors as well as via nuclear receptors. Currently, several COX-2-selective inhibitors are developed to control the anti-inflammatory and anti-neoplastic activities of the COX-2 isoenzyme. Inhibition of the COX isoenzyme activity and/or expression may be the basis of future generation of anti-inflammatory and anti-neoplastic drugs.
Assuntos
Isoenzimas/química , Isoenzimas/fisiologia , Prostaglandina-Endoperóxido Sintases/química , Prostaglandina-Endoperóxido Sintases/fisiologia , Animais , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Expressão Gênica , Humanos , Proteínas de Membrana , Modelos Biológicos , Peroxidases/fisiologiaRESUMO
PURPOSE: Two genes for adult-onset primary open-angle glaucoma have been mapped to chromosomes 2cen-q13 and 3q21-q24. We studied a family with adult-onset primary open-angle glaucoma in which the disease did not map to these two chromosomal regions. METHODS: We ascertained a four-generation family with adult-onset primary open-angle glaucoma in which the disease status of individuals was objectively assigned using defined criteria. Complete ophthalmologic examinations, visual field testing, optic nerve head photographs, and venous blood samples were obtained. Family members were genotyped using polymerase chain reaction amplification of microsatellite polymorphic markers. Linkage analysis was performed and lod scores were calculated. Haplotype transmission data were analyzed. RESULTS: A total of 20 subjects in three successive generations agreed to participate in the study. This included samples from eight affected subjects, one glaucoma suspect, one normal individual, and two spouses in generations II and III, and an additional eight individuals in generation IV. The phenotype in this family appears to be variable, with onset of visual field loss in middle age, followed by modest elevation of intraocular pressure and progression of the disease in older individuals. Linkage was established with a group of DNA markers located in the 8q23 region. A lod score value of 3.61 was obtained using marker D8S1471. Three other markers from the same region gave lod score values of over 3.0. Haplotype transmission data identified two recombination events that placed the gene in a 6.3-cM region flanked by D8S1830 and D8S592. The disease-bearing haplotype was inherited by eight affected subjects and three glaucoma suspects. CONCLUSION: We present evidence for a third adult-onset primary open-angle glaucoma locus (GLC1D) on chromosome 8q23. The genetic heterogeneity of adult-onset glaucoma is evident from the multiplicity of chromosomal loci associated with this disease.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 8 , Ligação Genética , Glaucoma de Ângulo Aberto/genética , Idoso , Doença Crônica , DNA/análise , Feminino , Marcadores Genéticos , Glaucoma de Ângulo Aberto/patologia , Haplótipos , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Disco Óptico/patologia , Linhagem , Reação em Cadeia da Polimerase , Sequências Repetitivas de Ácido Nucleico , Campos VisuaisRESUMO
One of the major causes of blindness is primary open-angle glaucoma, which affects millions of elderly people worldwide. Genetic studies have so far mapped three loci for the adult-onset form of this condition to the 2cen-q13, 3q21-q24, and 8q23 regions. Herein, we report the localization of a fourth locus, to the 10p15-p14 region, in one large British family with a classical form of normal-tension open-angle glaucoma. Of the 42 meioses genotyped in this pedigree, 39 subjects (16 affected) inherited a haplotype compatible with their prior clinical designation, whereas the remaining 3 were classified as unknown. Although a maximum LOD score of 10.00 at a recombination fraction of straight theta=.00 was obtained with D10S1216, 21 other markers provided significant values, varying between 3.77 and 9.70. When only the affected meioses of this kindred were analyzed, LOD scores remained statistically significant, ranging from 3.16 (D10S527) to 3.57 (D10S506). Two critical recombinational events in the affected subjects positioned this new locus to a region of approximately 21 cM, flanked by D10S1729 and D10S1664. However, an additional recombination in a 59-year-old unaffected female suggests that this locus resides between D10S585 (or D10S1172) and D10S1664, within a genetic distance of 5-11 cM. However, the latter minimum region must be taken cautiously, because the incomplete penetrance has previously been documented for this group of eye conditions. A partial list of genes that positionally are considered as candidates includes NET1, PRKCT, ITIH2, IL2RA, IL15RA, IT1H2, hGATA3, the mRNA for open reading frame KIAA0019, and the gene for D123 protein.
Assuntos
Cromossomos Humanos Par 10 , Glaucoma de Ângulo Aberto/genética , Adulto , Idade de Início , Idoso , Mapeamento Cromossômico , Feminino , Ligação Genética , Marcadores Genéticos , Genótipo , Haplótipos , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Fenótipo , Recombinação GenéticaRESUMO
Recent studies have indicated that repeated brief episodes of ischemia and reperfusion render the myocardium more tolerant to subsequent lethal ischemic injury. In view of the previous observations that ischemia-reperfusion potentiates phospholipase D signaling and that such signaling is beneficial for the heart, we investigated whether a similar phospholipase D signaling is responsible for the beneficial effects associated with repeated ischemia and reperfusion. Using an isolated perfused working rat heart model, we demonstrated that four brief episodes of 5 min of ischemia and 10 min of reperfusion reduced the incidence of ventricular arrhythmias, enhanced the postischemic ventricular performance, and decreased the release of creatine kinase from the reperfused heart, with simultaneous activation of phospholipase D generating the second messengers diacylglycerol and phosphatidic acid and leading to the translocation and activation of protein kinase C. The specific antiphospholipase D antibody blocked the activation of phospholipase D and attenuated the generation of diacylglycerol and phosphatidic acid and activation of protein kinase C. In concert, phospholipase D inhibition increased the incidence of ventricular arrhythmias, blocked the beneficial effects of preconditioning on the ventricular performance, and increased the amount of creatine kinase release from the coronary effluent. The results of this study indicate that repeated brief episodes of ischemia and reperfusion exert beneficial effects on the intact rat heart by triggering the activation of a phospholipase D signaling mechanism.
Assuntos
Precondicionamento Isquêmico , Miocárdio/enzimologia , Fosfolipase D/fisiologia , Transdução de Sinais/fisiologia , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Creatina Quinase/metabolismo , Técnicas In Vitro , Ácido Oleico/farmacologia , Fosfolipase D/imunologia , Ratos , Ratos Sprague-Dawley , Função Ventricular/efeitos dos fármacosAssuntos
Isquemia Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Fosfolipase D/metabolismo , Animais , Anticorpos/uso terapêutico , Técnicas In Vitro , Masculino , Isquemia Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fosfolipase D/imunologia , Ratos , Ratos Sprague-DawleyRESUMO
Primary open angle glaucoma (GLC1) is a common ocular disorder with a characteristic degeneration of the optic nerve and visual field defects that is often associated with an elevated intraocular pressure. The severe but rare juvenile-onset type has previously been mapped to 1q21-q31, and its genetic heterogeneity has been established. Herein, we present a new locus (GLC1B) for one form of GLC1 on chromosome 2cen-q13 with a clinical presentation of low to moderate intraocular pressure, onset in late 40s, and a good response to medical treatment. Two-point and haplotype analyses of affected and unaffected meioses in six families provided maximum linkage information with D2S417, GATA112EO3, D2S113, D2S373, and D2S274 (lod scores ranging from 3.11 to 6.48) within a region of 8.5 cM that is flanked by D2S2161 and D2S2264. Analysis of affected meioses alone revealed no recombination with an additional two markers (D2S2264 and D2S135) in a region of 11.2 cM that is flanked by D2S2161 and D2S176. Analysis of unaffected meioses identified only one healthy 86-year-old male who has inherited the entire affected haplotype and, hence, is a gene carrier for this condition. Eight additional families with similar and/or different clinical presentation did not show any linkage to this region and, therefore, provided evidence for genetic heterogeneity of adult-onset primary open angle glaucoma.
Assuntos
Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 2/genética , Glaucoma de Ângulo Aberto/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Centrômero/genética , Feminino , Triagem de Portadores Genéticos , Heterogeneidade Genética , Glaucoma de Ângulo Aberto/fisiopatologia , Haplótipos , Humanos , Escore Lod , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Linhagem , Polimorfismo GenéticoAssuntos
Traumatismo por Reperfusão Miocárdica/prevenção & controle , Niacinamida/análogos & derivados , Picolinas/farmacologia , Canais de Potássio/efeitos dos fármacos , Piranos/farmacologia , Animais , Técnicas In Vitro , Metabolismo dos Lipídeos , Isquemia Miocárdica , Miocárdio/metabolismo , Miocárdio/ultraestrutura , Niacinamida/farmacologia , Nicorandil , RatosRESUMO
The synthesis and the release of the atrial natriuretic factor (ANF) were studied by electron microscopy in the atrial cells from an ischemic myocardium. The ANF-containing secretory vesicles of normal atrial cells were present in great number near the Golgi apparatus, and near the sarcolemma. After 30 min. of global ischemia the number of ANF-containing secretory vesicles decreased in the atrial cells, suggesting an ANF release during heart ischemia.