Ronney A de Abreu

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Mercaptopurines have been used as anticancer agents for more than 40 years, and most acute lymphoblastic leukemias are treated with 6-mercaptopurine (6MP) or 6-thioguanine (TG). Overexpression of the two related multidrug resistance proteins MRP4 and MRP5 has been shown to confer some resistance against mercaptopurines, which has been attributed to(More)
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(More)
In the urine of a child with unexplained convulsions large amounts of uracil and thymine were detected by gas chromatography. Identification was performed by coupled gas chromatography-mass spectrometry. Quantitation of the urinary excretion by means of a sensitive high-performance liquid chromatographic (HPLC) method revealed a 1000-fold elevation compared(More)
The effects of prolonged exposure to 2 and 10 microM 6-mercaptopurine (6MP) in the human lymphoblastic T-cell line MOLT-4 were studied with respect to cell-kinetic parameters, phosphoribosyl pyrophosphate (PRPP) and purine ribonucleotide levels, formation of 6MP-nucleotides, especially methyl-thio-IMP (Me-tIMP), DNA and RNA synthesis ([32P] incorporation),(More)
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). A deficiency of DPD is increasingly being recognized as the cause of an important pharmacogenetic syndrome. The importance of DPD deficiency in the aetiology of unexpected severe 5FU toxicity has been demonstrated by the fact that, in(More)
OBJECTIVES To provide an update of the current knowledge of the mechanism of action of low-dose methotrexate (MTX) in the treatment of patients with rheumatoid arthritis (RA), with an emphasis on the mechanisms involved in toxicity. We also considered strategies currently used to prevent or decrease toxicity of MTX. METHODS We reviewed the literature(More)
The thiopurine antimetabolites 6-thioguanine and 6-mercaptopurine are important chemotherapeutic drugs in the treatment of childhood acute lymphoblastic leukaemia. Measurement of metabolites of these thiopurines is important because correlations exist between levels of these metabolites and the prognosis in childhood acute lymphoblastic leukaemia. The(More)
The studies described indicate that me-t-IMP formation is an important pathway, contributing to cytotoxicity in Molt F4 cells, which exhibit a highly active de novo purine synthesis. On three levels cytotoxicity is induced during methylation of thiopurines. 1. Purine synthesis de novo is inhibited during formation of me-t-IMP. Inhibition of PDNS results in(More)
6-Methylmercaptopurine ribonucleoside-5'-phosphate (MeSPuRMP), the sole metabolite of 6-methylmercaptopurine ribonucleoside (MeSPuRib), is a strong inhibitor of purine de novo synthesis, inducing depletion of intracellular purine nucleotides and subsequent cell death in several tumor cell lines. In this study prevention of MeSPuRib cytotoxicity by compounds(More)
Dihydropyrimidine dehydrogenase (DPD) is responsible for the breakdown of the widely used antineoplastic agent 5-fluorouracil (5-FU), thereby limiting the efficacy of the therapy. It has been suggested that patients suffering from 5-FU toxicities due to a low activity of DPD are genotypically heterozygous for a mutant allele of the gene encoding DPD. In(More)