ABSTRACT
After five decades since its approval, the anticancer drug 5-fluorouracil (5FU) still remains one of the most prescribed drugs in the chemotherapy of common cancers such as breast, colorectal, esophagogastric and head and neck cancers. Today, combination therapies of 5FU with for example anthracyclines or platinum drugs are predominantly being used, leading to improved therapeutic response rates. In addition, increased usage of oral prodrugs of 5-FU such as capecitabine is expected. However, therapeutic success is often limited by acute drug-adverse events, observed in up to
15-20% of the patients treated with 5FU. Frequently, these severe toxicities result in interruption of the chemotherapy and imply the risk of disease progression. Drug disposition and the efficacy/toxicity balance of 5FU are highly influenced by the action of dihydropyrimidine dehydrogenase (DPD), which constitutes the initial and rate-limiting step in the degradation of pyrimidines and fluoropyrimidines [10]. As such, high intratumoral DPD concentrations have been associated with low efficacy of a 5FU therapy. Furthermore, low tumoral DPD levels together with low thymidine phosphorylase (TP) and thymidylate synthase (TS) expression have been associated with a favorable treatment response [12,37]. Since more than 80% of administered 5FU is rapidly degraded by liver DPD, a general deficiency of this enzyme results in markedly prolonged exposure of the drug [10,28,45]. The main toxic reactions caused by reduced clearance of 5FU are myelosuppression, mucositis, diarrhea and neuropathy including also life-threatening events. Recent studies investigating the DPD status suggest that reduced DPD function may account for around 50% of the toxicity cases observed under 5FU therapy [8,49]. Besides DPD, variations in downstream acting enzymes of the pyrimidine catabolism such as dihydropyrimidase (DHP) and betaureidopropionase (BUP-1) may also contribute to some extent to an altered capacity to catabolize 5FU [41,42,55]. Regarding the high number of patients receiving 5FU-based therapies per year and the deleterious effects that are exerted by severe toxicities on their quality of life and disease cure, it is of major clinical interest to reduce the incidence of 5FU-related adverse events. To establish strategies for identifying high-risk patients, pharmacogenetic studies have mainly investigated the role of the gene encoding DPD (DPYD) and its mutational inactivation.
