Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU), and it is suggested that patients with a partial deficiency of this enzyme are at risk of developing severe 5-FU-associated toxicity. We evaluated the importance of DPD deficiency, gender and the presence of the IVS14؉1G>A mutation in the etiology of 5-FU toxicity. In 61% of cases, decreased DPD activity could be detected in peripheral blood mononuclear cells. Furthermore, the number of females (65%) in the total group of patients appeared to be higher than the number of males (35%) (p ‫؍‬ 0.03). Patients with partial DPD deficiency appeared to have a 3.4-fold higher risk of developing grade IV neutropenia than patients with normal DPD activity. Analysis of the DPYD gene of patients suffering from grade IV neutropenia for the presence of the IVS14؉1G>A mutation showed that 50% of the patients investigated were heterozygous or homozygous for the IVS14؉1G>A mutation. Adopting a threshold level for DPD activity of 70% of that observed in the normal population, 14% of the population is prone to the development of severe 5-FU-associated toxicity. Below this threshold level, 90% of individuals heterozygous for a mutation in the DPYD gene can be identified. Considering the common use of 5-FU in the treatment of cancer, the severe 5-FU-related toxicities in patients with low DPD activity and the apparently high prevalence of the IVS14؉1G>A mutation, screening of patients at risk before administration of 5-FU is warranted. © 2002 Wiley-Liss, Inc.Key words: dihydropyrimidine dehydrogenase; pharmacogenetics; 5-fluorouracil; neutropenia 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents for the systemic treatment of cancers arising from the gastrointestinal tract, breast, and head and neck. Due to the limited efficacy of 5-FU as a single drug, optimal administration schedules as well as combinations with other drugs have been investigated. 1,2 Long-term continuous i.v. infusion of 5-FU is superior to bolus injections in terms of response rate; however, only a small increase in median survival was observed. 1,2 To mimic the infusion schedules of 5-FU, prodrugs of 5-FU have been developed, which can be administered orally. In this respect, capecitabine has shown promising results in patients with advanced colorectal cancer and metastatic breast cancer. 3,4 Owing to the fact that 5-FU has a relatively narrow therapeutic index, toxicity increases as the dose is increased, resulting in escalated plasma levels of the drug. 5,6 Irrespective of the administration schedule of 5-FU or prodrugs thereof, 5-FU must first be metabolized to the nucleotide level to exert its cytotoxicity.An important determinant in predicting the toxicity as well as the efficacy of 5-FU might be the activity of dihydropyrimidine dehydrogenase (DPD). DPD is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil and thymine but also of the thymine analogue 5-FU. It has been report...

Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Linkage analysis in a Dutch family and an Australian family suggested that the candidate gene maps to Xq22.1-q24. Oligonucleotide microarray expression profiling of fibroblasts from two probands of the Dutch family revealed reduced expression levels of the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1). Subsequent sequencing of PRPS1 led to the identification of two different missense mutations, c.455T-->C (p.L152P) in the Dutch family and c.398A-->C (p.Q133P) in the Australian family. Both mutations result in a loss of phosphoribosyl pyrophosphate synthetase 1 activity, as was shown in silico by molecular modeling and was shown in vitro by phosphoribosyl pyrophosphate synthetase activity assays in erythrocytes and fibroblasts from patients. This is in contrast to the gain-of-function mutations in PRPS1 that were identified previously in PRPS-related gout. The loss-of-function mutations of PRPS1 likely result in impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. To replenish low levels of purines, treatment with S-adenosylmethionine theoretically could have therapeutic efficacy, and a clinical trial involving the two affected Australian brothers is currently underway.