Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). A deficiency of DPD is increasingly being recognized as the cause of an important pharmacogenetic syndrome. The importance of DPD deficiency in the aetiology of unexpected severe 5FU toxicity has been demonstrated by the fact that, in 39-;59% of cases, decreased DPD activity could be detected in peripheral blood mononuclear (PBM) cells. It was observed that 55% of the patients with a decreased DPD activity suffered from grade IV neutropenia compared with 13% of the patients with a normal DPD activity (P = 0·01). Furthermore, toxicity developed significantly earlier in patients with low DPD activity than in patients with normal DPD activity (10·0 ± 7·6 versus 19·1 ± 15·3 days, P < 0·05). In patients suffering from severe 5FU-associated toxicity, 11 mutations have been identified in DPYD, including one splice-site mutation (IVS14 + 1G→A), one nonsense mutation (E386X), four missense mutations (M166V, V335L, I560S, D949V) and five polymorphisms (C29R, R21Q, S534N, I543V, V732I). Considering the common use of 5FU in the treatment of cancer patients, the severe 5FU-related toxicities in patients with a low DPD activity and the high prevalence of the IVS14 + 1G→A mutation, analysis of the DPD activity in PBM cells or screening for the IVS14 + 1G→A mutation should be routinely carried out prior to the start of treatment with 5FU.

[1]  Hans R Waterham,et al.  Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene interpreted by analysis of the three-dimensional protein structure. , 2002, The Biochemical journal.

[2]  H. Groen,et al.  Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene , 2002, British Journal of Cancer.

[3]  R. Danesi,et al.  Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[4]  A. V. van Kuilenburg,et al.  Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5'-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)- related toxicity compared with controls. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[5]  F. Baas,et al.  Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[6]  A. Ganser,et al.  Safe administration of irinotecan, oxaliplatin and raltitrexed in a DPD-deficient patient with metastatic colon cancer. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[7]  P. Vreken,et al.  Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[8]  S. Groshen,et al.  Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[9]  H. McLeod,et al.  Known variant DPYD alleles do not explain DPD deficiency in cancer patients. , 2000, Pharmacogenetics.

[10]  Martin R. Johnson,et al.  Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[11]  M. Fukushima,et al.  Dihydropyrimidine dehydrogenase activity and messenger RNA level may be related to the antitumor effect of 5-fluorouracil on human tumor xenografts in nude mice. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[12]  E. Gamelin,et al.  Dose monitoring of 5-fluorouracil in patients with colorectal or head and neck cancer--status of the art. , 1999, Critical reviews in oncology/hematology.

[13]  Jason Lazarou,et al.  Incidence of Adverse Drug Reactions in Hospitalized Patients , 1999 .

[14]  H. Togari,et al.  Identification of novel mutations in the dihydropyrimidine dehydrogenase gene in a Japanese patient with 5-fluorouracil toxicity. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[15]  P. Vreken,et al.  Dihydropyrimidine dehydrogenase pharmacogenetics in Caucasian subjects. , 1998, British Journal of Clinical Pharmacology.

[16]  H. McLeod,et al.  Characterization of the human dihydropyrimidine dehydrogenase gene. , 1998, Genomics.

[17]  P. Vreken,et al.  Heterozygosity for a point mutation in an invariant splice donor site of dihydropyrimidine dehydrogenase and severe 5-fluorouracil related toxicity. , 1997, European journal of cancer.

[18]  P. Vreken,et al.  A point mutation in an invariant splice donor site leads to exon skipping in two unrelated Dutch patients with dihydropyrimidine dehydrogenase deficiency , 1996, Journal of Inherited Metabolic Disease.

[19]  H. McLeod,et al.  Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. , 1996, The Journal of clinical investigation.

[20]  E. Gamelin,et al.  Relationship between 5‐fluorouracil (5‐FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5‐FU , 1996, Cancer.

[21]  H. Pinedo,et al.  Do antimetabolites interfere with the glycosylation of cellular glycoconjugates? , 1990, European journal of cancer.

[22]  H. Pinedo,et al.  Fluorouracil: biochemistry and pharmacology. , 1988, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  R. Diasio,et al.  Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. , 1987, Cancer research.

[24]  R. Diasio,et al.  The effect of 5-fluorouracil on DNA chain elongation in intact bone marrow cells. , 1985, Biochemical and biophysical research communications.

[25]  D. Kessel Cell surface alterations associated with exposure of leukemia L1210 cells to fluorouracil. , 1980, Cancer research.

[26]  F Demard,et al.  Population study of dihydropyrimidine dehydrogenase in cancer patients. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  G. Peters,et al.  Clinical relevance of biochemical modulation of 5-fluorouracil. , 1991, Annals of oncology : official journal of the European Society for Medical Oncology.

[28]  Y. Cheng,et al.  Metabolism and mechanism of action of 5-fluorouracil. , 1990, Pharmacology & therapeutics.

[29]  R. Diasio,et al.  Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. , 1988, The Journal of clinical investigation.

[30]  R. Diasio,et al.  Alteration of the secondary structure of newly synthesized DNA from murine bone marrow cells by 5-fluorouracil. , 1986, Cancer research.