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Severe Drug Toxicity Associated with a Single-Nucleotide Polymorphism of the Cytidine Deaminase Gene in a Japanese Cancer Patient Treated with Gemcitabine plus Cisplatin

Authors' Affiliations: ¹ Division of Hepatobiliary and Pancreatic Oncology and ² Department of Medical Oncology, National Cancer Center Hospital; ³ Genetic Division, Research Institute, National Cancer Center, Tsukiji, Chuo-ku, Tokyo, Japan; ⁴ Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center East Hospital, Kashiwanoha, Kashiwa, Chiba, Japan, and ⁵ NIH Sciences, Kamiyoga, Setagaya-ku, Tokyo, Japan

Requests for reprints: Kan Yonemori, Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Phone: 81-3-3542-2511; Fax: 81-3-3542-3815; E-mail: kyonemor{at}ncc.go.jp.

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 µg hour/mL) was five times higher than the average value for five other patients (10.88 µg hour/mL) treated with gemcitabine plus cisplatin. The area under the concentration-time curve of 2',2'-difluorodeoxyuridine in this patient (41.58 µg hour/mL) was less than the half of the average value of the five patients (106.13 µg hour/mL). This patient was found to be homozygous for 208A (Thr⁷⁰) in the CDA gene, whereas the other patients were homozygous for 208G (Ala⁷⁰).

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.

Key Words: drug metabolism • chemotherapy • pharmacokinetics and pharmacogenomics

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