Page 12 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 1
Fluoropyrimidines
5-Fluorouracil (5-FU) and capecitabine belong to the group of fluoropyrimidines, which represent the backbone of anti-cancer treatment for various types of cancer, such as colorectal, breast and gastric cancer. Fluoropyrimidines are used by millions of patients worldwide each year1-3 and are often combined with other chemotherapeutic drugs (e.g. irinotecan or oxaliplatin), immunotherapeutic drugs or act as a radio-sensitizer in chemo- radiotherapy.4,5
5-FU was developed by Heidelberger et al. in the 1950’s.6 The anti-cancer effect of 5-FU is caused by three active metabolites, as shown in Figure 1. The first is 5-fluoro-2′-deoxyuridine- 5′-monophosphate (5-FdUMP), which inhibits the enzyme thymidylate synthase (TS). The inhibition of TS leads to a reduced production of deoxythymidine monophosphate (dTMP), resulting in the inhibition of DNA synthesis and repair. Two other metabolites, fluorouridine triphosphate (FUTP) and fluorodeoxyuridine triphosphate (FdUTP), are incorporated into RNA and DNA, respectively. This results in RNA and DNA damage and ultimately cell death.7
In February 2001, European approval and market authorization for Xeloda® (capecitabine) was given, the first oral pro-drug of 5-FU used in the treatment of metastatic colorectal cancer. Besides the advantage of oral administration, capecitabine is also a tumour-specific therapy for colorectal and breast cancer. Thymidine phosphorylase (TP), the third enzyme converting capecitabine into 5-FU, was found to be more expressed in breast and colorectal tumour cells compared to normal tissue. This leads to higher 5-FU levels in tumour cells compared to plasma, and thus a higher anti-cancer effect of capecitabine with less toxicity.8-10
5-FU has a relatively narrow therapeutic index and, depending on the type of treatment regimen, up to 30% of patients suffer from severe toxicity such as diarrhoea, nausea, (oral) mucositis, myelosuppression and hand-foot syndrome (HFS). These side-effects can lead to mortality in approximately 1% of patients.11,12 Toxicity is classified using the common terminology criteria for adverse events (CTC-AE) and grades 3 and higher are considered severe toxicity (range 0–5).
Dihydropyrimidine dehydrogenase
The enzyme dihydropyrimidine dehydrogenase (DPD) plays a key role in the metabolism of 5-FU. It is the rate limiting enzyme degrading over 80% of the drug into the inactive metabolite 5-fluoro-5,6-dihydrouracil (DHFU). Because of this, DPD plays an important role in the development of toxicity.13-16 DPD is mainly expressed in the liver, but also in other tissues.17,18 DPD shows great interpatient and intrapatient variability, is influenced by circadian rhythm19,20 and possibly gender.21-24 Some patients are partially DPD deficient (incidence 3–8%) or completely DPD deficient (incidence 0.2%).23-25 DPD deficient patients have higher levels of active 5-FU metabolites and therefore an increased risk to develop severe or even fatal fluoropyrimidine-induced toxicity.26-28 In addition, the onset of toxicity occurs faster in DPD deficient patients compared to patients with a normal DPD enzyme activity.28 Up to 60% of the patients who experienced severe fluoropyrimidine-induced toxicity were DPD deficient.21,22,27,28
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