RESUMO
PURPOSE: Fluoropyrimidines are one of the most used drug class to treat cancer patients, although they show high levels of associated toxicity. This study analyzed 33 polymorphisms in 17 pharmacogenes involved with the pharmacogenomics of fluoropyrimidines, in gastrointestinal cancer patients undergoing fluoropyrimidine-based treatment in the Brazilian Amazon. METHODS: The study population was composed of 216 patients, 92 of whom have an anatomopathological diagnosis of gastric cancer and 124 of colorectal cancer. The single nucleotide polymorphisms (SNP) were genotyped by allelic discrimination using the TaqMan OpenArray Genotyping technology, with a panel of 32 customized assays, run in a QuantStudio ™ 12K Flex Real-Time PCR System (Applied Biosystems, Life Technologies, Carlsbad USA). Ancestry analysis was performed using 61 autosomal ancestry informative markers (AIMs). RESULTS: The study population show mean values of 48.1% European, 31.1% Amerindian, and 20.8% African ancestries. A significant risk association for general and severe toxicity was found in the rs4451422 of FPGS (p = 0.001; OR 3.40; CI 95% 1.65-7.00 and p = 0.006; OR 4.63; CI 95% 1.56-13.72, respectively) and the rs9524885 of ABCC4 (p = 0.023; OR 2.74; CI 95% 1.14-6.65 and p = 0.024; OR 5.36; IC 95% 1.24-23.11, respectively) genes. The rs760370 in the SLC29A1 gene (p = 0.009; OR 6.71; CI 95% 1.16-8.21) and the rs1801133 in the MTHFR toxicity (p = 0.023; OR 3.09; CI 95% 1.16-8.21) gene also demonstrated to be significant, although only for severe toxicity. The results found in this study did not have statistics analysis correction. CONCLUSION: Four polymorphisms of the ABCC4, FPGS, SLC29A1, and MTHFR genes are likely to be potential predictive biomarkers for precision medicine in fluoropyrimidine-based treatments in the population of the Brazilian Amazon, which is constituted by a unique genetic background.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brasil , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Transportador Equilibrativo 1 de Nucleosídeo/genética , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Fluoruracila/farmacologia , Humanos , Leucovorina/farmacologia , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Compostos Organoplatínicos/farmacologia , Peptídeo Sintases/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
PURPOSE: The presence of deleterious variants of dihydropyrimidine-dehydrogenase gene (DPYD) is associated with 5-Fluorouracil toxicity. Most of the data are based on findings in Caucasian populations. The variant Y186C (rs115232898) is found almost exclusively in African populations and is related to low DPD function. Its prevalence may vary among African subpopulations and in African Americans. There is no information in other populations. Brazil has the biggest African population outside Africa. We studied for the first time the frequency of this mutation in African Brazilians. METHODS: We amplified exon 6 of DPYD extracted from genomic DNA of 79 healthy volunteers of genetically defined African ancestry from Southeast Brazil and 36 self-reported African descendants from Northeast Brazil in order to determine the prevalence of the variant Y186C in Brazilians of African ancestry. RESULTS: The variant Y186C was found in heterozygosity in two samples from Southeast (2.53%) and one from Northeast (2.77%) Brazil. Overall, the prevalence of this mutation in the 115 African Brazilians was 2.6%. CONCLUSIONS: The variant Y186C is prevalent among Brazilians of African ancestry and should be taken in account in targeted genotyping for fluoropyrimidine risk variants.
Assuntos
População Negra/genética , Deficiência da Di-Hidropirimidina Desidrogenase/etnologia , Di-Hidrouracila Desidrogenase (NADP)/genética , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/uso terapêutico , Brasil/epidemiologia , Capecitabina/farmacocinética , Capecitabina/uso terapêutico , Deficiência da Di-Hidropirimidina Desidrogenase/genética , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Feminino , Fluoruracila/farmacocinética , Fluoruracila/uso terapêutico , Voluntários Saudáveis , Humanos , Masculino , Mutação , Neoplasias/tratamento farmacológico , PrevalênciaAssuntos
Fármacos Dermatológicos/administração & dosagem , Dermatoses Faciais/tratamento farmacológico , Fluoruracila/administração & dosagem , Ceratose Actínica/tratamento farmacológico , Lasers de Estado Sólido/uso terapêutico , Dermatoses do Couro Cabeludo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Fármacos Dermatológicos/farmacocinética , Feminino , Fluoruracila/farmacocinética , Humanos , Masculino , Absorção Cutânea/efeitos da radiaçãoRESUMO
OBJECTIVE: to evaluate plasma and salivary uracil (U) to dihydrouracil (UH2) ratios as tools for predicting 5-fluorouracil systemic exposure and drug-related severe toxicity, and clinically validate the use of dried saliva spots (DSS) as an alternative sampling strategy for dihydropyrimidine dehydrogenase (DPD) deficiency assessment. METHODS: Pre-chemotherapy plasma, fresh saliva and DSS samples were obtained from gastrointestinal patients (Nâ¯=â¯40) for measurement of endogenous U and UH2 concentrations by LC-MS/MS. A second plasma sample collected during 5FU infusion was used for 5FU area under the curve (AUC) determination by HPLC-DAD. Data on toxicity was reported according to CTCAE. RESULTS: 15% of the patients developed severe 5FU-related toxicity, with neutropenia accounting for 67% of the cases. U, UH2 and [UH2,]/[U] were highly correlated between fresh and dried saliva samples (rsâ¯=â¯0.960; rsâ¯=â¯0.828; rsâ¯=â¯0.910, respectively). 5FU AUC ranged from 11.3 to 37.31â¯mgâ¯hâ¯L-1, with 46.2% of under-dosed and 10.3% over-dosed patients. The [UH2]/[U] ratios in plasma, fresh saliva and dried saliva samples were moderately correlated with 5FU AUC and adverse events grade, indicating a partial contribution of the variables to drug exposure (râ¯=â¯-0.412, rsâ¯=â¯-0.373, rsâ¯=â¯0.377) and toxicity (râ¯=â¯-0.363, rsâ¯=â¯-0.523, rsâ¯=â¯0.542). Metabolic ratios were lower in patients with severe toxicity (Pâ¯<â¯.01 salivary ratios, and Pâ¯<â¯.5 plasma ratios), and 5FU AUC were in average 47% higher in this group than in moderate toxicity. The diagnostic performance of [UH2]/[U] ratios in fresh saliva and DSS for the identification of patients with severe toxicity were comparable. CONCLUSIONS: The [UH2]/[U] metabolic ratios in plasma, fresh saliva and DSS were significantly associated with 5FU systemic exposure and toxicity degree. This study also demonstrated the applicability of DSS as alternative sampling for evaluating DPD activity.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Deficiência da Di-Hidropirimidina Desidrogenase/diagnóstico , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Fluoruracila/efeitos adversos , Neutropenia/induzido quimicamente , Saliva/metabolismo , Uracila/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Biomarcadores/sangue , Biomarcadores/metabolismo , Biotransformação , Deficiência da Di-Hidropirimidina Desidrogenase/sangue , Deficiência da Di-Hidropirimidina Desidrogenase/complicações , Deficiência da Di-Hidropirimidina Desidrogenase/metabolismo , Di-Hidrouracila Desidrogenase (NADP)/sangue , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Leucopenia/sangue , Leucopenia/induzido quimicamente , Leucopenia/metabolismo , Leucopenia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neutropenia/sangue , Neutropenia/metabolismo , Neutropenia/fisiopatologia , Índice de Gravidade de Doença , Caracteres Sexuais , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente , Trombocitopenia/metabolismo , Trombocitopenia/fisiopatologia , Uracila/análogos & derivados , Uracila/sangueRESUMO
Recent progress in medical knowledge has indicated that both clinical and biological markers will determine the response to different medical treatments: age, gender and genetics will determine the success of treatment. Genetic variability in this respect is fundamental and determines efficiency and safety of drugs, as well as susceptibility and illness' development. Fortunately, personalized medicine now offers individually tailored treatment strategies for each patient's needs. This is of outmost importance in oncology, since treatment is per se toxic and the commonly found low serum drug concentrations result in low treatment efficacy. Personalized medicine will allow a better approach to this, until now, a poorly managed disease. In this review we intent to raise awareness of personalized medicine and of clinical pharmacologic monitoring, with the aim to achieve adequate levels of efficacy and safety in the use of the cytotoxic drug 5-Fluorouracil (5-FU). Additionally, the importance of pharmacogenomics for the use of 5-FU is discussed. We designed this discussion towards medical practitioners challenged with treatment decisions every day, together with their patients.
Los pacientes bajo tratamiento con alopurinol pueden presentar reacciones adversas potencialmente mortales, particularmente al inicio del tratamiento. Las reacciones cutáneas adversas por alopurinol tienen una prevalencia aproximada del 2 %. Presentamos dos casos de síndrome de hipersensibilidad por alopurinol en pacientes mexicanos en quienes la hiperuricemia asintomática fue la indicación para su uso. El médico general y el especialista deben estar alerta ante este síndrome que ocasiona alta morbilidad y mortalidad.
Assuntos
Antineoplásicos/farmacocinética , Monitoramento de Medicamentos/métodos , Fluoruracila/farmacocinética , Medicina de Precisão/métodos , Antineoplásicos/sangue , Fluoruracila/sangue , Humanos , Testes FarmacogenômicosRESUMO
Poly(lactic acid) (PLA) or poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) blend nanoparticles were developed loading 5-fluorouracil (5-FU), an antitumor agent broadly used in therapy. A 2(3) factorial experimental design was conducted to indicate an optimal formulation and demonstrate the influence of the interactions of components on the mean particle size and drug encapsulation efficiency. Optimized PLA nanoparticles presented 294nm and 51% of 5-FU encapsulation efficiency and PLA-PEG blend nanoparticles presented 283nm and 55% of 5-FU encapsulation efficiency. In vitro release assay demonstrated after 320h about 50% of 5-FU was released from PLA and PLA-PEG blend nanoparticles. Release kinetics of 5-FU from nanoparticles followed second order and the release mechanism calculated by Korsmeyer-Peppas model was diffusion and erosion. In the assessment of cytotoxicity over Hep-2 tumor cells, PLA or PLA-PEG blend nanoparticles presented similar IC50 value than free 5-FU. Pharmacokinetic parameters after oral administration of 5-FU were improved by nanoencapsulation. Bioavailability, Cmax, Tmax, t1/2 and distribution volume were significantly improved, while clearance were decreased. PEG presence in nanoparticles didn't influence physicochemical and biological parameters evaluated. PLA and PLA-PEG nanoparticles can be potential carriers for oral delivery of 5-FU.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Fluoruracila/administração & dosagem , Nanopartículas/administração & dosagem , Poliésteres/administração & dosagem , Polietilenoglicóis/administração & dosagem , Animais , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Portadores de Fármacos/farmacocinética , Fluoruracila/sangue , Fluoruracila/farmacocinética , Humanos , Masculino , Poliésteres/farmacocinética , Polietilenoglicóis/farmacocinética , Ratos WistarRESUMO
PURPOSE: Intestinal mucositis (IM) is a common side effect of anticancer agents. Despite polychemotherapy use in clinical practice, the pathogenesis of IM has been investigated in single drug injection animal models. However, the progression of IM could vary according to drug regimens. Thus, we aimed to develop a new experimental mucositis model induced by combining irinotecan and 5-fluorouracil (5-FU) treatments. METHODS: IM was induced in male C57BL/6 mice by the intraperitoneal administration of either 0.9 % saline (5 mL/kg), irinotecan (IRI, 30 or 45 mg/kg), 5-FU (25, 37.5, or 50 mg/kg), or the combination of these doses (IRI + 5-FU) for 4 days. Animal survival, body mass variation, and diarrhea scores were evaluated daily. On the 7th day, the mice were euthanized, and intestinal samples were collected for histopathology and morphometric analysis, as well as for the determination of myeloperoxidase activity and cytokine dosage (TNF-α and IL-6). RESULTS: The optimal dose combination that induced IM and presented no substantial mortality on the 7th day was IRI (45 mg/kg) + 5-FU (37.5 mg/kg), which was used for subsequent studies. IRI and 5-FU in combination induced significant diarrhea, body weight loss, intestinal damage, inflammatory cell infiltration, and increased levels of cytokines when compared with other groups (P < 0.05). Neither IRI nor 5-FU alone induced IM. CONCLUSIONS: We developed a new experimental model of IM induced by combining irinotecan and 5-FU treatments, which will allow us to gain a better knowledge concerning the pathogenesis of this disease through the pharmacological modulation of key inflammatory mediators.
Assuntos
Camptotecina/análogos & derivados , Fluoruracila , Mucosa Intestinal , Mucosite , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Diarreia , Relação Dose-Resposta a Droga , Esquema de Medicação , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Interleucina-6/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Irinotecano , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Mucosite/induzido quimicamente , Mucosite/metabolismo , Mucosite/fisiopatologia , Peroxidase/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Para fundamentar as ações de cuidado integralizado em saúde da mulher é necessário compreender de que modo o apoio social pode contribuir para minimizar as repercussões do diagnóstico e do tratamento da neoplasia mamária. O objetivo deste estudo é analisar a contribuição da produção científica nacional e internacional acerca do apoio social percebido por mulheres diagnosticadas com câncer de mama. A amostra foi constituída de 12 publicações, obtidas a partir de critérios de inclusão preestabelecidos, nas bases de dados MedLine, Lilacs e PsycINFO, na última década (2000-2010). Os resultados foram sistematizados em categorias temáticas: percepção do apoio familiar, apoio social percebido, percepção do apoio educacional, necessidade de aprimoramento da pesquisa e assistência às mastectomizadas e suas famílias. Os estudos dedicados à dimensão subjetiva do apoio social ainda são incipientes. As evidências disponíveis sugerem que a literatura é circunscrita a temas de interesse das profissões tradicionais da área da saúde, como Enfermagem e Medicina, privilegiando construtos que podem ser diretamente quantificados. A preocupação com o apoio social deve estar presente desde a fase de diagnóstico até a reabilitação psicossocial, como parte do processo de enfrentamento.
It is necessary to understand how social support can contribute to minimize the impact of the diagnosis and treatment of mammary tumors in order to underpin the actions of comprehensive women's health care. This study seeks to analyze the contribution of the national and international literature regarding the perceived social support by women diagnosed with breast cancer. Twelve studies were selected from the MedLine, Lilacs and PsycINFO databases over a 10-year period (2000-2010) with pre-defined criteria for inclusion. The results were organized into thematic categories: the perception of family support; perceived social support; the perception of educational support; the need to improve the research and the assistance given to women after mastectomy and their families. The studies dedicated to the subjective dimension of social support are still incipient. The available evidence suggests that the literature is limited to topics of interest to the traditional health professions, such as Nursing and Medicine, focusing on constructs that can be directly quantified. The concern with social support must be present from the time of diagnosis to psychosocial rehabilitation, as part of the process of tackling the situation.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Fatores Etários , Antimetabólitos Antineoplásicos/uso terapêutico , Área Sob a Curva , Capecitabina , Neoplasias Colorretais/metabolismo , Desoxicitidina/sangue , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Floxuridina/sangue , Fluoruracila/sangue , Fluoruracila/farmacocinética , Fluoruracila/uso terapêutico , Taxa de Filtração Glomerular , Taxa de Depuração Metabólica , Fatores SexuaisRESUMO
Objetivou-se identificar comportamentos e práticas sexuais de homens que fazem sexo com homens no contexto da vulnerabilidade ao HIV/AIDS. Estudo transversal, exploratório descritivo. Foi realizado em um local de sociabilidade gay de Fortaleza, no Estado do Ceará, entre novembro de 2010 e março de 2011, por meio de entrevista com 189 homens que fazem sexo com homens. Encontrou-se uma amostra composta, majoritariamente, por jovens, solteiros e com alto nível educacional. A história sexual demonstrou o início precoce da vida sexual, com prevalência elevada de relação sexual com parceira do sexo oposto. Houve alta frequência de testagem para o HIV. As práticas sexuais revelaram prevalência superior da realização de sexo oral e anal, bem como altos níveis de proteção no sexo anal, apesar de baixa no sexo oral. Constatou-se uma maior incorporação das práticas de prevenção em relação ao panorama nacional do início da epidemia.
The objective was to identify behaviors and sexual practices of men who have sexual relations with other men in the context of vulnerability to HIV/AIDS. This was a cross-sectional, exploratory and descriptive study. It was carried out in a gay sociability place in Fortaleza, Ceará, Brazil, between November 2010 and March 2011, through interviews with 189 men who have sex with men. The ethical aspects were respected. We found a sample consisting mostly by young, single, and highly educated men. The sexual history demonstrated the early onset of sexual activity, with a high prevalence of sexual intercourse with a partner of the opposite sex. There was also a high prevalence of HIV testing. Sexual practices revealed high prevalence of performing oral and anal sex, as well as high levels of protection in anal sex, despite the low protection in oral sex. A greater incorporation of prevention practices was found compared to the national scene in the beginning of the disease outbreak.
El objetivo fue identificar los comportamientos y las prácticas sexuales de los hombres que tienen sexo con hombres en el contexto de la vulnerabilidad al VIH/SIDA. Fue un estudio transversal, descriptivo y exploratorio. Se celebró en una sociabilidad local gay de Fortaleza, Ceará, Brasil, entre noviembre de 2010 y marzo de 2011, a través de entrevistas con 189 hombres que tienen sexo con hombres. Se encontró una muestra compuesta en su mayoría por jóvenes, solteros y con alto nivel de educación. La historia sexual demostró el inicio temprano de la actividad sexual, la alta prevalencia de relaciones sexuales con una pareja del sexo opuesto. Hubo alta prevalencia de la prueba del VIH. Las prácticas sexuales revelaron una alta prevalencia de realizar sexo oral y anal, así como altos niveles de protección en el sexo anal, a pesar de la baja protección en el sexo oral. Se encontró una mayor incorporación de las prácticas de prevención en relación con la escena nacional en el inicio de la epidemia.
Assuntos
Animais , Feminino , Ratos , Fluoruracila/farmacocinética , Fígado/efeitos dos fármacos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Tumor Carcinoide/tratamento farmacológico , Tumor Carcinoide/metabolismo , Floxuridina/farmacocinética , Floxuridina/uso terapêutico , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Infusões Intravenosas , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Neoplasias Experimentais/tratamento farmacológico , Ratos Endogâmicos , Tegafur/farmacocinética , beta-Alanina/análise , beta-Alanina/análogos & derivados , beta-Alanina/biossínteseRESUMO
Gastric cancer (GC) is often diagnosed at later stages due to the lack of specificity of symptoms associated with the neoplasm, causing high mortality rates worldwide. The first line of adjuvant and neoadjuvant treatment includes cytotoxic fluoropyrimidines and platin-containing compounds which cause the formation of DNA adducts. The clinical outcome with these antineoplastic agents depends mainly on tumor sensitivity, which is conditioned by the expression level of the drug targets and the DNA-repair system enzymes. In addition, some germ line polymorphisms, in genes linked to drug metabolism and response to chemotherapy, have been associated with poor responses and the development of adverse effects, even with fatal outcomes in GC patients. The identification of genomic biomarkers, such as individual gene polymorphisms or differential expression patterns of specific genes, in a patient-by-patient context with potential clinical application is the main focus of current pharmacogenomic research, which aims at developing a rational and personalized therapy (i.e., a therapy that ensures maximum efficacy with no predictable side effects). However, because of the future application of genomic technologies in the clinical setting, it is necessary to establish the prognostic value of these genomic biomarkers with genotype-phenotype association studies and to evaluate their prevalence in the population under treatment. These issues are important for their cost-effectiveness evaluation, which determines the feasibility of using these medical genomic research products for GC treatment in the clinical setting.