Top

Cancer Chemotherapy and Pharmacology

Published in:

01-07-2009 | Short Communication

Lack of large intragenic rearrangements in dihydropyrimidine dehydrogenase (DPYD) gene in fluoropyrimidine-treated patients with high-grade toxicity

Authors: Ivana Ticha, Petra Kleiblova, Julie Fidlerova, Jan Novotny, Petr Pohlreich, Zdenek Kleibl

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2009

Abstract

Purpose

Deficiency of dihydropyrimidine dehydrogenase (DPD) has been associated with severe fluoropyrimidines (FP) toxicity. Mutations in DPD-coding gene (DPYD) were shown to increase the risk of severe toxicity in FP-treated cancer patients. However, the majority of DPYD alterations characterized in these patients has been considered as polymorphisms and known deleterious mutations are rare and present in only limited subgroup of patients with high toxicity. Recently, the common fragile site FRA1E was mapped within DPYD locus but intragenic rearrangements in DPYD gene were not studied so far.

Methods

We performed the analysis of intragenic rearrangements of DPYD using multiplex ligation-dependent probe amplification in 68 patients with high-grade gastrointestinal and/or hematological toxicity developed at the beginning of FP treatment.

Results

We did not detect any deletion/duplication of one or more DPYD exons in analyzed patients.

Conclusions

We assume that rearrangements in DPYD gene play insignificant role in the development of serious FP-related toxicity.

van Kuilenburg AB (2004) Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer 40:939–950PubMedCrossRef

Diasio RB (1998) Sorivudine and 5-fluorouracil; a clinically significant drug-drug interaction due to inhibition of dihydropyrimidine dehydrogenase. Br J Clin Pharmacol 46:1–4PubMedCrossRef

Collie-Duguid ES, Etienne MC, Milano G et al (2000) Known variant DPYD alleles do not explain DPD deficiency in cancer patients. Pharmacogenetics 10:217–223PubMedCrossRef

Maekawa K, Saeki M, Saito Y et al (2007) Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences. J Hum Genet 52:804–819PubMedCrossRef

Schwab M, Zanger UM, Marx C et al (2008) Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU toxicity study group. J Clin Oncol 26:2131–2138PubMedCrossRef

Bosch TM, Bakker R, Schellens JH et al (2007) Rapid detection of the DPYD IVS14 + 1G > A mutation for screening patients to prevent fluorouracil-related toxicity. Mol Diagn Ther 11:105–108PubMed

Johnson MR, Wang K, Tillmanns S et al (1997) Structural organization of the human dihydropyrimidine dehydrogenase gene. Cancer Res 57:1660–1663PubMed

Hormozian F, Schmitt JG, Sagulenko E et al (2007) FRA1E common fragile site breaks map within a 370kilobase pair region and disrupt the dihydropyrimidine dehydrogenase gene (DPYD). Cancer Lett 246:82–91PubMedCrossRef

den Dunnen JT, White SJ (2006) MLPA and MAPH: sensitive detection of deletions and duplications. In: Ujhazy V (ed) Current protocols in human genetics, Wiley, New York, pp 7.14.1–7.14.20

10.

Kleibl Z, Fidlerova J, Kleiblova P et al (2009) Influence of dihydropyrimidine dehydrogenase gene (DPYD) coding sequence variants on the development of fluoropyrimidine-related toxicity in patients with high-grade toxicity and patients with excellent tolerance of fluoropyrimidine-based chemotherapy. Neoplasma 56 (accepted)

11.

MRC-Holland. http://www.mlpa.com/, SALSA MLPA kit P103 DPYD

12.

Ploylearmsaeng SA, Fuhr U, Jetter A (2006) How may anticancer chemotherapy with fluorouracil be individualised? Clin Pharmacokinet 45:567–592PubMedCrossRef

13.

Maring JG, van Kuilenburg AB, Haasjes J et al (2002) Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene. Br J Cancer 86:1028–1033PubMedCrossRef

14.

Ezzeldin HH, Diasio RB (2008) Predicting fluorouracil toxicity: can we finally do it? J Clin Oncol 26:2080–2082PubMedCrossRef

15.

Mercier C, Ciccolini J (2006) Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy. Clin Colorectal Cancer 6:288–296PubMedCrossRef

16.

Saif MW, Ezzeldin H, Vance K et al (2007) DPYD*2A mutation: the most common mutation associated with DPD deficiency. Cancer Chemother Pharmacol 60:503–507PubMedCrossRef

17.

van Kuilenburg AB, Meinsma R, Zoetekouw L et al (2002) High prevalence of the IVS14 + 1G > A mutation in the dihydropyrimidine dehydrogenase gene of patients with severe 5-fluorouracil-associated toxicity. Pharmacogenetics 12:555–558PubMedCrossRef

18.

Morel A, Boisdron-Celle M, Fey L et al (2006) Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther 5:2895–2904PubMedCrossRef

19.

Gross E, Busse B, Riemenschneider M et al (2008) Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients. PLoS ONE 3:e4003PubMedCrossRef

20.

Imyanitov EN, Moiseyenko VM (2007) Molecular-based choice of cancer therapy: realities and expectations. Clin Chim Acta 379:1–13PubMedCrossRef

Title: Lack of large intragenic rearrangements in dihydropyrimidine dehydrogenase (DPYD) gene in fluoropyrimidine-treated patients with high-grade toxicity
Authors: Ivana Ticha
Petra Kleiblova
Julie Fidlerova
Jan Novotny
Petr Pohlreich
Zdenek Kleibl
Publication date: 01-07-2009
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2009
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-009-0970-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2009

Tumor specific cytotoxicity of β-glucosylceramide: structure–cytotoxicity relationship and anti-tumor activity in vivo

Oral administration of the GnRH antagonist acyline, in a GIPET®-enhanced tablet form, acutely suppresses serum testosterone in normal men: single-dose pharmacokinetics and pharmacodynamics

Role of frequency and mechanical index in ultrasonic-enhanced chemotherapy in rats

Response of imatinib-resistant extra-abdominal aggressive fibromatosis to sunitinib: case report and review of the literature on response to tyrosine kinase inhibitors

Expression of ERCC1 and class III β-tubulin in non-small cell lung cancer patients treated with a combination of cisplatin/docetaxel and concurrent thoracic irradiation

Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of tumors implanted in rat livers by inducing platinum-DNA adducts to form and massive apoptosis

Keynote webinar | Spotlight on antibody–drug conjugates in cancer