Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene

5-fluorouracil pharmacokinetics, dihydropyrimidine dehydrogenase-activity and DNA sequence analysis were compared between a patient with extreme 5-fluorouracil induced toxicity and six control patients with normal 5-fluorouracil related symptoms. Patients were treated for colorectal cancer and recei...

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Autores principales: Maring, J G, van Kuilenburg, A B P, Haasjes, J, Piersma, H, Groen, H J M, Uges, D R A, Van Gennip, A H, De Vries, E G E
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2002
Materias:
Clinical
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2364178/
https://www.ncbi.nlm.nih.gov/pubmed/11953843
http://dx.doi.org/10.1038/sj.bjc.6600208
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author Maring, J G
van Kuilenburg, A B P
Haasjes, J
Piersma, H
Groen, H J M
Uges, D R A
Van Gennip, A H
De Vries, E G E
author_facet Maring, J G
van Kuilenburg, A B P
Haasjes, J
Piersma, H
Groen, H J M
Uges, D R A
Van Gennip, A H
De Vries, E G E
author_sort Maring, J G
collection PubMed
description 5-fluorouracil pharmacokinetics, dihydropyrimidine dehydrogenase-activity and DNA sequence analysis were compared between a patient with extreme 5-fluorouracil induced toxicity and six control patients with normal 5-fluorouracil related symptoms. Patients were treated for colorectal cancer and received chemotherapy consisting of leucovorin 20 mg m(−2) plus 5-fluorouracil 425 mg m(−2). Blood sampling was carried out on day 1 of the first cycle. The 5-fluorouracil area under the curve(0→3h) in the index patient was 24.1 mg h l(−1) compared to 9.8±3.6 (range 5.4–15.3) mg h l(−1) in control patients. The 5-fluorouracil clearance was 520 ml min(−1) vs 1293±302 (range 980–1780) ml min(−1) in controls. The activity of dihydropyrimidine dehydrogenase in mononuclear cells was lower in the index patient (5.5 nmol mg h(−1)) compared to the six controls (10.3±1.6, range 8.0–11.7 nmol mg h(−1)). Sequence analysis of the dihydropyrimidine dehydrogenase gene revealed that the index patient was heterozygous for a IVS14+1G>A point mutation. Our results indicate that the inactivation of one dihydropyrimidine dehydrogenase allele can result in a strong reduction in 5-fluorouracil clearance, causing severe 5-fluorouracil induced toxicity. British Journal of Cancer (2002) 86, 1028–1033. DOI: 10.1038/sj/bjc/6600199 www.bjcancer.com © 2002 Cancer Research UK
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spelling pubmed-23641782009-09-10 Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene Maring, J G van Kuilenburg, A B P Haasjes, J Piersma, H Groen, H J M Uges, D R A Van Gennip, A H De Vries, E G E Br J Cancer Clinical 5-fluorouracil pharmacokinetics, dihydropyrimidine dehydrogenase-activity and DNA sequence analysis were compared between a patient with extreme 5-fluorouracil induced toxicity and six control patients with normal 5-fluorouracil related symptoms. Patients were treated for colorectal cancer and received chemotherapy consisting of leucovorin 20 mg m(−2) plus 5-fluorouracil 425 mg m(−2). Blood sampling was carried out on day 1 of the first cycle. The 5-fluorouracil area under the curve(0→3h) in the index patient was 24.1 mg h l(−1) compared to 9.8±3.6 (range 5.4–15.3) mg h l(−1) in control patients. The 5-fluorouracil clearance was 520 ml min(−1) vs 1293±302 (range 980–1780) ml min(−1) in controls. The activity of dihydropyrimidine dehydrogenase in mononuclear cells was lower in the index patient (5.5 nmol mg h(−1)) compared to the six controls (10.3±1.6, range 8.0–11.7 nmol mg h(−1)). Sequence analysis of the dihydropyrimidine dehydrogenase gene revealed that the index patient was heterozygous for a IVS14+1G>A point mutation. Our results indicate that the inactivation of one dihydropyrimidine dehydrogenase allele can result in a strong reduction in 5-fluorouracil clearance, causing severe 5-fluorouracil induced toxicity. British Journal of Cancer (2002) 86, 1028–1033. DOI: 10.1038/sj/bjc/6600199 www.bjcancer.com © 2002 Cancer Research UK Nature Publishing Group 2002-04-08 /pmc/articles/PMC2364178/ /pubmed/11953843 http://dx.doi.org/10.1038/sj.bjc.6600208 Text en Copyright © 2002 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Clinical
Maring, J G
van Kuilenburg, A B P
Haasjes, J
Piersma, H
Groen, H J M
Uges, D R A
Van Gennip, A H
De Vries, E G E
Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene
title Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene
title_full Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene
title_fullStr Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene
title_full_unstemmed Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene
title_short Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene
title_sort reduced 5-fu clearance in a patient with low dpd activity due to heterozygosity for a mutant allele of the dpyd gene
topic Clinical
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2364178/
https://www.ncbi.nlm.nih.gov/pubmed/11953843
http://dx.doi.org/10.1038/sj.bjc.6600208
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