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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

DPD-dependent inactivation of 5-FU and effects of DPD deficiency. For abbreviations, see Fig. 1
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Fig2: DPD-dependent inactivation of 5-FU and effects of DPD deficiency. For abbreviations, see Fig. 1

Mentions: The pharmacological activity of fluoropyrimidines (Fig. 1) depends on the transformation of 5–FU into his active metabolite 5–fluoro–deoxyuridine monophosphate (5–FdUMP), which forms a stable complex with reduced folates and thymidylate synthase (TS), the key enzyme for de novo synthesis of thymidine. The inhibition of TS leads to the arrest of DNA synthesis, an effect further enhanced by the intracellular generation of fluoropyrimidine deoxynucleotide analogues which are incorporated into DNA and RNA leading to their disruption [4, 5]. It is worth noting that the activity of fluoropyrimidines depends on the equilibrium between anabolic and catabolic pathways. In particular, more than 80% of an administered dose of 5–FU is transformed to inactive metabolites, being the remaining 20% or less responsible for the therapeutic effect (Fig. 1). The first step of 5-FU biotransformation is catalyzed by the enzyme dihydropyrimidine dehydrogenase (DPD, Fig. 2), which is also involved in the catabolism of thymine and uracil. The degradation of uracil is responsible for the endogenous biosynthesis of β-alanine, a structural analogue of two inhibitory neurotransmitters, glycine and γ-aminobutyric acid (GABA). 5–FU is transformed by DPD into 5–fluoro–5,6–dihydrouracil (5–FDHU), which is further metabolized to α-fluoro–β–alanine (FBAL) by two additional enzymes and finally excreted by the kidneys. The profound deficit in DPD activity is a well known metabolic syndrome of children characterized by thymine–uraciluria, mental retardation and high levels of thymine and uracil in blood, urines and cerebrospinal fluid. Therefore, the administration of fluoropyrimidines to patients with a deficient DPD activity potentially results in life–threatening toxicities, because a larger amount of 5–FU is activated to cytotoxic metabolites (Fig. 2). Capecitabine is an orally administered inactive prodrug that is enzymatically converted into 5-FU [6]. Thymidine phosphorylase (TP) is expressed at high levels in the liver and many tumors and catalyzes the bioactivation of capecitabine preferentially in cancer tissue, leading to high concentrations of 5-FU in tumor cells [3, 5].Fig. 1


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)

DPD-dependent inactivation of 5-FU and effects of DPD deficiency. For abbreviations, see Fig. 1
© Copyright Policy
Related In: Results  -  Collection

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

Fig2: DPD-dependent inactivation of 5-FU and effects of DPD deficiency. For abbreviations, see Fig. 1
Mentions: The pharmacological activity of fluoropyrimidines (Fig. 1) depends on the transformation of 5–FU into his active metabolite 5–fluoro–deoxyuridine monophosphate (5–FdUMP), which forms a stable complex with reduced folates and thymidylate synthase (TS), the key enzyme for de novo synthesis of thymidine. The inhibition of TS leads to the arrest of DNA synthesis, an effect further enhanced by the intracellular generation of fluoropyrimidine deoxynucleotide analogues which are incorporated into DNA and RNA leading to their disruption [4, 5]. It is worth noting that the activity of fluoropyrimidines depends on the equilibrium between anabolic and catabolic pathways. In particular, more than 80% of an administered dose of 5–FU is transformed to inactive metabolites, being the remaining 20% or less responsible for the therapeutic effect (Fig. 1). The first step of 5-FU biotransformation is catalyzed by the enzyme dihydropyrimidine dehydrogenase (DPD, Fig. 2), which is also involved in the catabolism of thymine and uracil. The degradation of uracil is responsible for the endogenous biosynthesis of β-alanine, a structural analogue of two inhibitory neurotransmitters, glycine and γ-aminobutyric acid (GABA). 5–FU is transformed by DPD into 5–fluoro–5,6–dihydrouracil (5–FDHU), which is further metabolized to α-fluoro–β–alanine (FBAL) by two additional enzymes and finally excreted by the kidneys. The profound deficit in DPD activity is a well known metabolic syndrome of children characterized by thymine–uraciluria, mental retardation and high levels of thymine and uracil in blood, urines and cerebrospinal fluid. Therefore, the administration of fluoropyrimidines to patients with a deficient DPD activity potentially results in life–threatening toxicities, because a larger amount of 5–FU is activated to cytotoxic metabolites (Fig. 2). Capecitabine is an orally administered inactive prodrug that is enzymatically converted into 5-FU [6]. Thymidine phosphorylase (TP) is expressed at high levels in the liver and many tumors and catalyzes the bioactivation of capecitabine preferentially in cancer tissue, leading to high concentrations of 5-FU in tumor cells [3, 5].Fig. 1

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