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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

Macroscopic appearance of a palmar region of a patient with severe hand foot syndrome
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Fig3: Macroscopic appearance of a palmar region of a patient with severe hand foot syndrome

Mentions: The typical toxicity in a poor or DPD metabolizer occurs at the first cycle of chemotherapy and it is characterized by grade 4 (WHO) symptoms and potentially death. Most frequent reported side effects are diarrhea grade 3 or 4, complete alopecia, mucositis grade 3 or 4, hand-foot syndrome (Fig. 3) and neutropenia grade 3–4 [21]. Shahrokni et al. reported a case of a patient who developed recurrent chest pain and ischemic electrocardiogram changes after treatment with 5-FU and capecitabine. Cardiotoxicity associated with 5-FU and capecitabine administration is infrequently reported in the literature and appears to be dose and schedule-dependent [22]. Öfverholm et al. described a patient given adjuvant chemotherapy of weekly bolus injections of 500 mg/m2 5-FU and 20 mg/m2 folinic acid; after being asymptomatic throughout the first 2 cycles, on days 3–5 after the third cycle he experienced mild stomatitis and watering eyes. The symptoms rapidly worsened and he was admitted to hospital care for 3 weeks with grade 3–4 oral mucositis and grade 3–4 diarrhea. After 1 month of recovery, the treatment was reintroduced with a 50% dose reduction, a dose he could tolerate with only minor degree of toxicity until the end of the treatment period [23]. Another patient treated with adjuvant 5-FU 500 mg/m2 i.v. and folinic acid 60 mg/m2 i.v. on days 1 and 2, every 2 weeks, experienced grade 3 severe fatigue and grade 2 watering eyes after two thirds of treatment [23]. Morel et al. described a patient who died from severe, polyvisceral failure following the first administration of 5-FU 400 mg/m2 i.v. bolus, and 22 h-infusion of 5-FU 600 mg/m2, plus 400 mg/m2 leucovorin. Seven days after the first cycle, he was hospitalized because of grade 4 diarrhea, mucositis, grade 4 leuko/thrombocytopenia, and dehydration. He then developed renal insufficiency and died 7 days later, 19 days after 5-FU administration, despite intensive supportive treatment [24].Fig. 3


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)

Macroscopic appearance of a palmar region of a patient with severe hand foot syndrome
© Copyright Policy
Related In: Results  -  Collection

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

Fig3: Macroscopic appearance of a palmar region of a patient with severe hand foot syndrome
Mentions: The typical toxicity in a poor or DPD metabolizer occurs at the first cycle of chemotherapy and it is characterized by grade 4 (WHO) symptoms and potentially death. Most frequent reported side effects are diarrhea grade 3 or 4, complete alopecia, mucositis grade 3 or 4, hand-foot syndrome (Fig. 3) and neutropenia grade 3–4 [21]. Shahrokni et al. reported a case of a patient who developed recurrent chest pain and ischemic electrocardiogram changes after treatment with 5-FU and capecitabine. Cardiotoxicity associated with 5-FU and capecitabine administration is infrequently reported in the literature and appears to be dose and schedule-dependent [22]. Öfverholm et al. described a patient given adjuvant chemotherapy of weekly bolus injections of 500 mg/m2 5-FU and 20 mg/m2 folinic acid; after being asymptomatic throughout the first 2 cycles, on days 3–5 after the third cycle he experienced mild stomatitis and watering eyes. The symptoms rapidly worsened and he was admitted to hospital care for 3 weeks with grade 3–4 oral mucositis and grade 3–4 diarrhea. After 1 month of recovery, the treatment was reintroduced with a 50% dose reduction, a dose he could tolerate with only minor degree of toxicity until the end of the treatment period [23]. Another patient treated with adjuvant 5-FU 500 mg/m2 i.v. and folinic acid 60 mg/m2 i.v. on days 1 and 2, every 2 weeks, experienced grade 3 severe fatigue and grade 2 watering eyes after two thirds of treatment [23]. Morel et al. described a patient who died from severe, polyvisceral failure following the first administration of 5-FU 400 mg/m2 i.v. bolus, and 22 h-infusion of 5-FU 600 mg/m2, plus 400 mg/m2 leucovorin. Seven days after the first cycle, he was hospitalized because of grade 4 diarrhea, mucositis, grade 4 leuko/thrombocytopenia, and dehydration. He then developed renal insufficiency and died 7 days later, 19 days after 5-FU administration, despite intensive supportive treatment [24].Fig. 3

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