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1.
Int J Mol Med ; 2(4): 477-82, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9857238

RESUMO

Dihydropyrimidine dehydrogenase (DPD) deficiency with a defect of the pyrimidine catabolic pathway has recently become the focus of considerable attention, due to the severe 5-fluorouracil (5-FU) toxicities occurring in DPD deficiency patients. Studies also suggest that 5-FU toxicities could occur in another pyrimidine metabolic disorder, dihydropyrimidinuria (DHPuria). This study shows that urinary dihydrothymine (DHT) and thymine (THY) are useful indexes for detection of DPD deficiency and DHPuria. We measured urinary DHT and THY in 276 Japanese adults to establish reference ranges. When males and females were compared, both DHT and THY levels were found to be significantly higher in females. The reference ranges (mean +/- SD with logarithmic values) for males were found to be 1.56-5.70 micromol/g of creatinine for DHT and 0.40-1.47 micromol/g of creatinine for THY. The reference ranges for females were found to be 1.89-8.33 micromol/g of creatinine for DHT and 0.58-2.30 micromol/g of creatinine for THY. In addition to this study we analyzed a DPD deficiency case and a DHPuria case. In the DPD deficiency case, the THY concentrations of all urine samples were out of the reference range. However, uracil levels in most of the samples were within the normal range. The DHPuria case excreted large amounts of DHT and dihydrouracil, both out of the normal range.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Fluoruracila/efeitos adversos , Timina/urina , Adolescente , Adulto , Criança , Pré-Escolar , Deficiência da Di-Hidropirimidina Desidrogenase , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/urina , Pirimidinas/urina , Valores de Referência
2.
Clin Cancer Res ; 4(12): 2999-3004, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9865912

RESUMO

5-Fluorouracil (5-FU) is used widely in the treatment of several common neoplasms. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. Several recent studies have described a pharmacogenetic disorder in which cancer patients with decreased DPD activity develop life-threatening toxicity following exposure to 5-FU. We reported recently the first Japanese case of decreased DPD activity accompanied by severe 5-FU toxicity. The present study describes the results of molecular analysis of this patient and her family, in which three novel mutations (Arg21Gln, Val335Leu, and Glu386Ter) of the gene coding for DPD were identified. We also revealed that Arg21Gln and Glu386Ter are on the same allele and that Val335Leu is on the other allele, on the basis of analysis of the family genome. Expression analysis in Escherichia coli showed that Val335Leu and Glu386Ter led to mutant DPD protein with significant loss of enzymatic activity and no activity, respectively. The Arg21Gln mutation, however, resulted in no decrease in enzymatic activity compared with the wild type. The present data represent the first molecular genetic analysis of DPD deficiency accompanied by severe 5-FU toxicity in a Japanese patient.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Neoplasias da Mama/enzimologia , Fluoruracila/efeitos adversos , Oxirredutases/genética , Antimetabólitos Antineoplásicos/uso terapêutico , Sequência de Bases , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Catálise , Análise Mutacional de DNA , DNA Complementar/análise , Di-Hidrouracila Desidrogenase (NADP) , Feminino , Fluoruracila/uso terapêutico , Humanos , Japão , Pessoa de Meia-Idade , Dados de Sequência Molecular , Oxirredutases/deficiência , Oxirredutases/metabolismo , Pirimidinas/urina , Análise de Sequência de DNA
3.
Am J Hum Genet ; 63(3): 717-26, 1998 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9718352

RESUMO

Dihydropyrimidinase (DHP) deficiency (MIM 222748) is characterized by dihydropyrimidinuria and is associated with a variable clinical phenotype. This disease might be associated with a risk of 5-fluorouracil toxicity, although no cases have been reported. We present here both the molecular characterization of the human DHP gene and, for the first time, the mutations causing DHP deficiency. The human DHP gene spans >80 kb and consists of 10 exons. It has been assigned to 8q22, by FISH. We performed mutation analysis of genomic DNA in one symptomatic and five asymptomatic individuals presenting with dihydropyrimidinuria. We identified one frameshift mutation and five missense mutations. Two related Japanese adult subjects were homozygous for the Q334R substitution, whereas two other, unrelated Japanese infant subjects were heterozygous for the same mutation, but this mutation is not common in the Japanese population. A Caucasian pediatric patient exhibiting epileptic attacks, dysmorphic features, and severe developmental delay was homozygous for W360R. Using a eukaryotic expression system, we showed that all mutations reduced enzyme activity significantly, indicating that these are crucial DHP deficiency-causing mutations. There was no significant difference, in residual activity, between mutations observed in the symptomatic and those observed in the asymptomatic individuals.


Assuntos
Amidoidrolases/deficiência , Amidoidrolases/genética , Cromossomos Humanos Par 8 , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Adulto , Amidoidrolases/biossíntese , Animais , Sequência de Bases , Células COS , Criança , Mapeamento Cromossômico , Clonagem Molecular , Análise Mutacional de DNA , Éxons , Feminino , Mutação da Fase de Leitura , Homozigoto , Humanos , Hibridização in Situ Fluorescente , Japão , Cariotipagem , Masculino , Mutagênese Sítio-Dirigida , Linhagem , Erros Inatos do Metabolismo da Purina-Pirimidina/enzimologia , Proteínas Recombinantes/biossíntese , Transfecção
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