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2.
Autops. Case Rep ; 8(4): e2018049, Oct.-Dec. 2018. ilus, graf
Artigo em Inglês | LILACS | ID: biblio-986574

RESUMO

5-Fluorouracil (5-FU), in combination with other cytotoxic drugs, is commonly used to treat a variety of cancers. Dihydropyrimidine dehydrogenase (DPD) catalyzes the first catabolic step of the 5-FU degradation pathway, converting 80% of 5-FU to its inactive metabolite. Approximately 0.3% of the population demonstrate complete DPD deficiency, translating to extreme toxicity of 5-FU. Here we present a case of a patient who had a fatal outcome after treatment with 5-FU who was found to have an unknown DPD deficiency discovered at autopsy.


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Deficiência da Di-Hidropirimidina Desidrogenase/patologia , Fluoruracila/toxicidade , Neoplasias de Cabeça e Pescoço , Autopsia , Evolução Fatal , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Deficiência da Di-Hidropirimidina Desidrogenase/tratamento farmacológico , Fluoruracila/uso terapêutico , Linfonodos
3.
Int J Cancer ; 142(2): 424-430, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28929491

RESUMO

Fluoropyrimidines are frequently used anti-cancer drugs. It is known that patients with reduced activity of dihydropyrimidine dehydrogenase (DPD), the key metabolic enzyme in fluoropyrimidine inactivation, are at increased risk of developing severe fluoropyrimidine-related toxicity. Upfront screening for DPD deficiency and dose reduction in patients with partial DPD deficiency is recommended and improves patient safety. For patients with complete DPD deficiency, fluoropyrimidine-treatment has generally been discouraged. During routine pretreatment screening, we identified a 59-year-old patient with a sigmoid adenocarcinoma who proved to have a complete DPD deficiency. Genetic analyses showed that this complete absence of DPD activity was likely to be caused by a novel DPYD genotype, consisting of a combination of amplification of exons 17 and 18 of DPYD and heterozygosity for DPYD*2A. Despite absence of DPD activity, the patient was treated with capecitabine-based chemotherapy, but capecitabine dose was drastically reduced to 150 mg once every 5 days (0.8% of original dose). Pharmacokinetic analyses showed that the area under the concentration-time curve (AUC) and half-life of 5-fluorouracil were respectively tenfold and fourfold higher than control values of patients receiving capecitabine 850 mg/m2 . When extrapolating from the dosing schedule of once every 5 days to twice daily, the AUC of 5-fluorouracil was comparable to controls. Treatment was tolerated well for eight cycles by the patient without occurrence of capecitabine-related toxicity. This case report demonstrates that a more comprehensive genotyping and phenotyping approach, combined with pharmacokinetically-guided dose administration, enables save fluoropyrimidine-treatment with adequate drug exposure in completely DPD deficient patients.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Capecitabina/uso terapêutico , Deficiência da Di-Hidropirimidina Desidrogenase/tratamento farmacológico , Di-Hidrouracila Desidrogenase (NADP)/genética , Deficiência da Di-Hidropirimidina Desidrogenase/genética , Deficiência da Di-Hidropirimidina Desidrogenase/patologia , Feminino , Testes Genéticos , Genótipo , Humanos , Pessoa de Meia-Idade , Prognóstico
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