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Dihydropyrimidine dehydrogenase polymorphisms and fluoropyrimidine toxicity: ready for routine clinical application within personalized medicine?

Del Re M, Di Paolo A, van Schaik RH, Bocci G, Simi P, Falcone A, Danesi R - EPMA J (2010)

Bottom Line: Fluoropyrimidines, including 5-fluorouracil (5-FU), are widely used in the treatment of solid tumors and remain the backbone of many combination regimens.Despite their clinical benefit, fluoropyrimidines are associated with gastrointestinal and hematologic toxicities, which often lead to treatment discontinuation. 5-FU undergoes complex metabolism, dihydropyrimidine dehydrogenase (DPD) being the rate-limiting enzyme of inactivation of 5-FU and its prodrugs.To date, more than 30 SNPs and deletions have been identified within DPD, the majority of these variants having no functional consequences on enzymatic activity.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacology, Department of Internal Medicine, University of Pisa, 55, Via Roma, 56126 Pisa, Italy.

ABSTRACT
Fluoropyrimidines, including 5-fluorouracil (5-FU), are widely used in the treatment of solid tumors and remain the backbone of many combination regimens. Despite their clinical benefit, fluoropyrimidines are associated with gastrointestinal and hematologic toxicities, which often lead to treatment discontinuation. 5-FU undergoes complex metabolism, dihydropyrimidine dehydrogenase (DPD) being the rate-limiting enzyme of inactivation of 5-FU and its prodrugs. Several studies have demonstrated significant associations between severe toxicities by fluoropyrimidines and germline polymorphisms of DPD gene. To date, more than 30 SNPs and deletions have been identified within DPD, the majority of these variants having no functional consequences on enzymatic activity. However, the identification of deficient DPD genotypes may help identify poor-metabolizer patients at risk of developing potentially life-threatening toxicities after standard doses of fluoropyrimidines.

No MeSH data available.


Related in: MedlinePlus

Proposed algorithm for screening DPD deficiency and dose adjustment in patients
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Fig5: Proposed algorithm for screening DPD deficiency and dose adjustment in patients

Mentions: While the uracil breath test and plasma uracil quantitation to stratify patients for their risk of incurring in fluoropyrimidine-induced toxicity are useful with some important limitations, the genomic approach appears to be superior for indirect assessment of DPD. Although most of the informations come from case reports or a few published articles, the available clinical evidences obtained either prospectively or retrospectively clearly identify IVS14 + 1G > A as the most important mutation causing severe toxicity or even death. Therefore, IVS14 + 1G > A testing should be performed in patients before the first administration of fluoropyrimidines or in those who suffered from severe toxicities. The preliminary screening of other variants associated with less-severe adverse drug reactions before the commencement of therapy is not justified. The following approach may be suggested for patients never treated with fluoropyrimidines or with fluoropyrimidine-induced toxicity (Fig. 5). New patients are screened for the most important and potentially lethal IVS14 + 1G > A mutation. If they are negative, they may be treated with standard doses of the drugs and then screened afterwards for other DPD variants if they display toxicity after the first doses of treatment. If they are heterozygous for IVS14 + 1G > A, the dose should be reduced at least empirically or, preferably, after accurate assessment of residual metabolic activity by DPD enzyme activity of 5-FU-test dose (Fig. 5). If a patient treated with fluoropyrimidines displays toxicity, he should be screened at least for the variants listed in Table 1. If heterozygous for IVS14 + 1G > A or hetero- or homozygous for other variants, he should be treated by empirically reduced drug dose of after phenotypic assessment (enzymatic DPD activity measurement or 5-FU pharmacokinetics). In all cases, patients homozygous for IVS14 + 1G > A must not be treated with fluoropyrimidines.Fig. 5


Dihydropyrimidine dehydrogenase polymorphisms and fluoropyrimidine toxicity: ready for routine clinical application within personalized medicine?

Del Re M, Di Paolo A, van Schaik RH, Bocci G, Simi P, Falcone A, Danesi R - EPMA J (2010)

Proposed algorithm for screening DPD deficiency and dose adjustment in patients
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3405332&req=5

Fig5: Proposed algorithm for screening DPD deficiency and dose adjustment in patients
Mentions: While the uracil breath test and plasma uracil quantitation to stratify patients for their risk of incurring in fluoropyrimidine-induced toxicity are useful with some important limitations, the genomic approach appears to be superior for indirect assessment of DPD. Although most of the informations come from case reports or a few published articles, the available clinical evidences obtained either prospectively or retrospectively clearly identify IVS14 + 1G > A as the most important mutation causing severe toxicity or even death. Therefore, IVS14 + 1G > A testing should be performed in patients before the first administration of fluoropyrimidines or in those who suffered from severe toxicities. The preliminary screening of other variants associated with less-severe adverse drug reactions before the commencement of therapy is not justified. The following approach may be suggested for patients never treated with fluoropyrimidines or with fluoropyrimidine-induced toxicity (Fig. 5). New patients are screened for the most important and potentially lethal IVS14 + 1G > A mutation. If they are negative, they may be treated with standard doses of the drugs and then screened afterwards for other DPD variants if they display toxicity after the first doses of treatment. If they are heterozygous for IVS14 + 1G > A, the dose should be reduced at least empirically or, preferably, after accurate assessment of residual metabolic activity by DPD enzyme activity of 5-FU-test dose (Fig. 5). If a patient treated with fluoropyrimidines displays toxicity, he should be screened at least for the variants listed in Table 1. If heterozygous for IVS14 + 1G > A or hetero- or homozygous for other variants, he should be treated by empirically reduced drug dose of after phenotypic assessment (enzymatic DPD activity measurement or 5-FU pharmacokinetics). In all cases, patients homozygous for IVS14 + 1G > A must not be treated with fluoropyrimidines.Fig. 5

Bottom Line: Fluoropyrimidines, including 5-fluorouracil (5-FU), are widely used in the treatment of solid tumors and remain the backbone of many combination regimens.Despite their clinical benefit, fluoropyrimidines are associated with gastrointestinal and hematologic toxicities, which often lead to treatment discontinuation. 5-FU undergoes complex metabolism, dihydropyrimidine dehydrogenase (DPD) being the rate-limiting enzyme of inactivation of 5-FU and its prodrugs.To date, more than 30 SNPs and deletions have been identified within DPD, the majority of these variants having no functional consequences on enzymatic activity.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacology, Department of Internal Medicine, University of Pisa, 55, Via Roma, 56126 Pisa, Italy.

ABSTRACT
Fluoropyrimidines, including 5-fluorouracil (5-FU), are widely used in the treatment of solid tumors and remain the backbone of many combination regimens. Despite their clinical benefit, fluoropyrimidines are associated with gastrointestinal and hematologic toxicities, which often lead to treatment discontinuation. 5-FU undergoes complex metabolism, dihydropyrimidine dehydrogenase (DPD) being the rate-limiting enzyme of inactivation of 5-FU and its prodrugs. Several studies have demonstrated significant associations between severe toxicities by fluoropyrimidines and germline polymorphisms of DPD gene. To date, more than 30 SNPs and deletions have been identified within DPD, the majority of these variants having no functional consequences on enzymatic activity. However, the identification of deficient DPD genotypes may help identify poor-metabolizer patients at risk of developing potentially life-threatening toxicities after standard doses of fluoropyrimidines.

No MeSH data available.


Related in: MedlinePlus