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Genetic polymorphisms of dihydropyrimidinase in a Japanese patient with capecitabine-induced toxicity.
Hiratsuka, Masahiro; Yamashita, Hiroshi; Akai, Fumika; Hosono, Hiroki; Hishinuma, Eiji; Hirasawa, Noriyasu; Mori, Takahiro.
Afiliación
  • Hiratsuka M; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
  • Yamashita H; Department of Surgery, Iwate Prefectural Chubu Hospital, Kitakami, Japan.
  • Akai F; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
  • Hosono H; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
  • Hishinuma E; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
  • Hirasawa N; Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
  • Mori T; Graduate School of Medicine, Tohoku University, Sendai, Japan.
PLoS One ; 10(4): e0124818, 2015.
Article en En | MEDLINE | ID: mdl-25915935
ABSTRACT
Dihydropyrimidinase (DHP) is the second enzyme in the catabolic pathway of uracil, thymine, and chemotherapeutic fluoropyrimidine agents such as 5-fluorouracil (5-FU). Thus, DHP deficiency might be associated with 5-FU toxicity during fluoropyrimidine chemotherapy. We performed genetic analyses of the family of a patient with advanced colon cancer who underwent radical colectomy followed by treatment with 5-FU prodrug capecitabine and developed severe toxicity attributable to a lack of DHP. We measured urinary uracil and dihydrouracil, and genotyped DPYS in the patient and her family. We also measured the allele frequency of DPYS polymorphisms in 391 unrelated Japanese subjects. The patient had compound heterozygous missense and nonsense polymorphisms comprising c.1001A>G (p.Gln334Arg) in exon 6 and c.1393C>T (p.Arg465Ter) in exon 8, which are known to result in a DHP enzyme with little or no activity. The urinary dihydrouracil/uracil ratio in the patient was 17.08, while the mean ± SD urinary dihydrouracil/uracil ratio in family members who were heterozygous or homozygous for wild-type DPYS was 0.25 ± 0.06. In unrelated subjects, 8 of 391 individuals were heterozygous for the c.1001A>G mutation, while the c.1393C>T mutation was not identified. This is the first report of a DHP-deficient patient with DPYS compound heterozygous polymorphisms who was treated with a fluoropyrimidine, and our findings suggest that polymorphisms in the DPYS gene are pharmacogenomic markers associated with severe 5-FU toxicity in Japanese patients.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias del Colon / Polimorfismo de Nucleótido Simple / Pueblo Asiatico / Capecitabina / Amidohidrolasas / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Adult / Aged / Female / Humans / Male / Middle aged País/Región como asunto: Asia Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2015 Tipo del documento: Article País de afiliación: Japón

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias del Colon / Polimorfismo de Nucleótido Simple / Pueblo Asiatico / Capecitabina / Amidohidrolasas / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Adult / Aged / Female / Humans / Male / Middle aged País/Región como asunto: Asia Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2015 Tipo del documento: Article País de afiliación: Japón