Impact of cytidine deaminase genetic polymorphisms on gemcitabine kinetics and toxicity in Japanese cancer patients

Abstract

2009 Background: Gemcitabine is an anti-cancer drug effective against solid tumors. It is rapidly metabolized to its inactive metabolite 2’,2’-difluorodeoxyuridine (dFdU) by cytidine deaminase (CDA), for which several genetic polymorphisms are known. We investigated the impact of genetic polymorphisms of CDA on gemcitabine pharmacokinetics and toxicities. Methods: Two hundred fifty-two Japanese cancer patients who had not previously received gemcitabine were given a 30-min i.v. infusion of the drug at either 800 or 1000 mg/m2, and blood samples were collected before the infusion, at 3 min before the end of the infusion, and 15, 30, 60, 90, 120, and 240 min after the end of the infusion. Plasma levels of gemcitabine and its metabolite were measured by HPLC. Plasma CDA activity was also measured using gemcitabine as a substrate. Polymorphisms of the CDA gene were detected by a dideoxy sequencing method using genomic DNA obtained from peripheral blood leukocytes. Results: Two non-synonymous genetic polymorphisms of CDA - 79A>C (*2, K27Q) and 208G>A (*3, A70T) were found, and their allele frequencies were 0.207 and 0.037, respectively. Pharmacokinetic parameters and plasma CDA activities were significantly dependent on the *3 allele (Results of preliminary analysis are summarized in the Table. The data will be fixed by the meeting). In a patient homozygous for *3, very severe toxicities including grade 4 neutropenia, grade 4 thrombocytopenia, and grade 3 rash were observed. The *2 allele had no marked effects on the pharmacokinetics or toxicities of gemcitabine. Conclusions: Carriers of the CDA *3 allele have decreased clearance of gemcitabine. Attention should therefore be given to patients with the CDA *3 allele before commencing gemcitabine treatment. No significant financial relationships to disclose.