Abstract
Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%–30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients’ homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies’ results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer.
| Original language | English |
|---|---|
| Pages (from-to) | 8884-8895 |
| Number of pages | 12 |
| Journal | International Journal of Molecular Sciences |
| Volume | 16 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 21 2015 |
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Keywords
- Dihydropyrimidine dehydrogenase
- Fluoropyrimidines
- Pharmacogenetics
- Single nucleotide polymorphisms
- Toxicity
ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Organic Chemistry
- Spectroscopy
- Inorganic Chemistry
- Catalysis
- Molecular Biology
- Computer Science Applications
Cite this
Undetected toxicity risk in pharmacogenetic testing for dihydropyrimidine dehydrogenase. / Falvella, Felicia Stefania; Caporale, Marta; Cheli, Stefania; Martinetti, Antonia; Berenato, Rosa; Maggi, Claudia; Niger, Monica; Ricchini, Francesca; Bossi, Ilaria; Di Bartolomeo, Maria; Sottotetti, Elisa; Bernardi, Francesca Futura; de Braud, Filippo; Clementi, Emilio; Pietrantonio, Filippo.
In: International Journal of Molecular Sciences, Vol. 16, No. 4, 21.04.2015, p. 8884-8895.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Undetected toxicity risk in pharmacogenetic testing for dihydropyrimidine dehydrogenase
AU - Falvella, Felicia Stefania
AU - Caporale, Marta
AU - Cheli, Stefania
AU - Martinetti, Antonia
AU - Berenato, Rosa
AU - Maggi, Claudia
AU - Niger, Monica
AU - Ricchini, Francesca
AU - Bossi, Ilaria
AU - Di Bartolomeo, Maria
AU - Sottotetti, Elisa
AU - Bernardi, Francesca Futura
AU - de Braud, Filippo
AU - Clementi, Emilio
AU - Pietrantonio, Filippo
PY - 2015/4/21
Y1 - 2015/4/21
N2 - Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%–30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients’ homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies’ results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer.
AB - Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%–30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients’ homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies’ results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer.
KW - Dihydropyrimidine dehydrogenase
KW - Fluoropyrimidines
KW - Pharmacogenetics
KW - Single nucleotide polymorphisms
KW - Toxicity
UR - http://www.scopus.com/inward/record.url?scp=84928139184&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84928139184&partnerID=8YFLogxK
U2 - 10.3390/ijms16048884
DO - 10.3390/ijms16048884
M3 - Article
VL - 16
SP - 8884
EP - 8895
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 4
ER -