Pharmacogenetic screening of docetaxel, irinotecan and fluoropyrimidines in cancer therapy

Abstract

In this thesis the pharmacogenetic screening of drug metabolising enzymes and drug transporters in healthy volunteers and in patients treated with docetaxel, irinotecan or fluoropyrimidines are described. Pharmacogenetic screening in cancer treatment and cancer risk In chapter 1, an overview of the earlier published results about pharmacogenetic screening in cancer treatment and cancer risk is presented. A number of polymorphisms have been described in genes coding for drug metabolising enzymes and drug transporters. However, in most cases no clear association has been found for polymorphisms in these enzymes and pharmacokinetics and pharmacodynamics of anticancer drugs. Pharmacogenetic screening in healthy volunteers In chapter 2.1 the allelic frequencies and linkage disequilibrium of polymorphisms in drug metabolising enzymes (CYP1A1, CYP2C9, CYP2C19, CYP3A4, CYP2D6, CYP3A5, DPYD, UGT1A1, GSTM1, GSTP1 and GSTT1) and drug transporters (MDR1 and MRP2) were explored in 100 Dutch healthy volunteers. 16 New polymorphisms were identified. Two of the new polymorphisms resulted in an amino acid change (A428T in CYP2C9 resulting in D143V and C4461T in MRP2 causing an amino acid change of T1476M). The BCRP gene was also screened (chapter 2.2). In total, 19 polymorphisms were found, of which 7 were previously unknown. The polymorphisms G8883A and C44168T caused an amino acid change of R160Q and R575X, respectively. The frequencies of polymorphisms in the PXR gene was determined (chapter 2.3). In total, 24 polymorphisms were found in this gene, of which 9 are previously unknown. One new polymorphism, T8555G, causes an amino acid change of C379G. Pharmacogenetic screening in docetaxel treatment The influence of polymorphisms in the CYP3A and MDR1 genes on the population pharmacokinetics of docetaxel was described in chapter 3.1. The homozygous mutant C1236T polymorphisms in the MDR1 gene was significantly correlated with a decreased docetaxel clearance (-25%; p=0.0039). Pharmacogenetic screening in irinotecan treatment In chapter 4.1, the study to determine whether a correlation exists between the polymorphisms in the UGT1A1 and MRP2 genes and different bilirubin patterns found in human serum was described. We found a trend that patients homozygous mutant for UGT1A1*28 have higher unconjugated bilirubin levels and lower mono- and di-glucuronide levels of bilirubin than heterozygous mutant or wild-type patients. However, this effect was not statistically significant. The influence of polymorphisms in the CYP3A4, UGT1A1, MDR1, MRP2 and BCRP genes on the population pharmacokinetics of irinotecan and its metabolites (SN-38 and SN-38G) was described in chapter 4.2. The SN-38 clearance was decreased for UGT1A1*28 heterozygous and homozygous mutant patients, however, this effect was not statistically significant. Pharmacogenetic screening in treatment with fluoropyrimidines In chapter 5.1 the correlation between polymorphisms in the DPYD gene and the dihydropyrimidine dehydrogenase (DPD) activity, was described, in patients treated with 5-FU or capecitabine with and without severe 5-FU-related toxicity. All five patients with the GIVS14+1A mutation experienced severe 5-FU-related toxicity and the mean hospitalisation duration was 18 days (patients without this mutation had to be hospitalised for only 2.5 days.