An Investigation of the Effect of the Promoter Polymorphism in the Glucuronosyltransferase 2B7 Using Epirubicin Clearance and the Ratios of Epirubicin and Epirubicinol Glucuronide to Epirubicin

Epirubicin is an anthracycline that is widely used in breast cancer, stomach and esophageal cancer. Despite epirubicin being the 4'-epi-isomer of doxorubicin, epirubicin undergoes substantially different metabolism compared to doxorubicin. The majority of epirubicin is metabolized to glucuronides, 78.0% to epirubicin glucuronide and 19.3% to epirubicinol glucuronide and only 0.2% epirubicin is metabolized to epirubicinol. Doxorubicin is primarily metabolized to aglycones or doxorubicinol but not to glucuronides. There is substantial variability in epirubicin metabolism with the mean clearance of 84.6 L/h and a standard deviation of 63.5. A study by Hu et al showed epirubicin metabolism correlated with response. In this study they showed patients with nasopharyngeal cancer treated with epirubicin were more likely to relapse if they rapidly metabolized epirubicin. A study by Robert et al raises the possibility that the differences in epirubicin metabolism are determined by genetic differences. They showed a bimodal distribution in the ratio of epirubicin glucuronides to epirubicin. As well this study showed that low glucuronidation were more likely to respond to epirubicin than patients who had a high ratio of epirubicin glucuronides to epirubicin. Innocenti et al has shown that epirubicin is metabolized to its glucuronides by uridine glucuronosyltransferase 2B7 (UGT2B7). The same study showed a strong correlation between the formation of morphine-6-glucuronide and the glucuronidation of epirubicin in human liver microsomes. The researchers have recently discovered a single nucleotide polymorphism in the enhancer region of UGT 2B7. Patients who were homozygous for this polymorphism tended to have lower ratios of morphine-6-glucuronide to morphine. The researchers suspect that this T to C polymorphism decreases the transcription of UGT 2B7 and this is the basis of the decreased glucuronidation. Given the strong correlation between the metabolism of morphine and epirubicin in human liver microsomes the researchers suspect that this polymorphism may be responsible for the variability in epirubicin metabolism. Previous work has documented an overlapping bimodal distribution in the ratio of epirubicin glucuronides but they did not examine whether genetic polymorphisms were responsible for this. This study will examine the effect of this polymorphism on the metabolism of epirubicin. If a relationship exists between this polymorphism and epirubicin metabolism this may allow more accurate dosing of this important chemotherapeutic agent.

Objectives:

To determine in patients receiving adjuvant intravenous FEC chemotherapy (5-Fluoruracil 500 mg/m2, epirubicin 100 mg/m2, Cyclophosphamide 500 mg/m2) given every 3 weeks whether the newly discovered SNP at position -161 T to C is responsible for the variability in epirubicin metabolism.

Participants:

Patients receiving adjuvant FEC chemotherapy. Patients can not have pre-existing liver disease other than Gilbert's syndrome. In patients with a history of liver disease, liver transaminases must be less than 3 times the upper limit of normal and bilirubin less than the upper limit of normal. Patients must be >/= 18 years of age.