Severe drug toxicity associated with a single-nucleotide polymorphisrn of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin

Purpose: We investigated single-nucleotide polymorphisms of the cytidine deaminase gene (CDA), which encodes an enzyme that metabolizes gemcitabine, to clarify the relationship between the single-nucleotide polymorphism 208G>A and the pharmacokinetics and toxicity of gemcitabine in cancer patients treated with gemcitabine plus cisplatin. Experimental Design: Six Japanese cancer patients treated with gemcitabine plus cisplatin were examined. Plasma gemcitabine and its metabolite 2',2'-difluorodeoxyuridine were measured using an high-performance liquid chromatography method, and the CDA genotypes were determined with DNA sequencing. Results: One patient, a 45-year-old man with pancreatic carcinoma, showed severe hematologic and nonhematologic toxicities during the first course of chemotherapy with gemcitabine and cisplatin. The area under the concentration-time curve value of gemcitabine in this patient (54.54 mu g hour/mL) was five times higher than the average value for five other patients (10.88 mu g hour/mL) treated with gemcitabine plus cisplatin. The area under the concentration-time curve of 2,2'-difluorodeoxyuridine in this patient (41.58 mu g hour/mL) was less than the half of the average value of the five patients (106.13 mu g hour/mL). This patient was found to be homozygous for 208A (Thr(70)) in the CDA gene, whereas the other patients were homozygous for 208G (Ala(70)). Conclusion: Homozygous 208G>A alteration in CDA might have caused the severe drug toxicity experienced by a Japanese cancer patient treated with gemcitabine plus cisplatin.