This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gilbert, J. A. Articles by Weinshilboum, R. M. Search for Related Content PubMed PubMed Citation Articles by Gilbert, J. A. Articles by Weinshilboum, R. M.

Gemcitabine Pharmacogenomics: Cytidine Deaminase and Deoxycytidylate Deaminase Gene Resequencing and Functional Genomics

Authors' Affiliations: Departments of ¹ Molecular Pharmacology and Experimental Therapeutics and ² Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota

Requests for reprints: Richard M. Weinshilboum, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-2246; Fax: 507-284-9111; E-mail: Weinshilboum.Richard{at}mayo.edu.

Purpose: Gemcitabine is a nucleoside analogue with activity against solid tumors. Gemcitabine metabolic inactivation is catalyzed by cytidine deaminase (CDA) or, after phosphorylation, by deoxycytidylate deaminase (DCTD). We set out to study the pharmacogenomics of CDA and DCTD.

Experimental Design: The genes encoding CDA and DCTD were resequenced using DNA from 60 African American and 60 Caucasian American subjects. Expression constructs were created for nonsynonymous coding single nucleotide polymorphisms (cSNP) and reporter gene constructs were created for 5'-flanking region polymorphisms. Functional genomic studies were then conducted after the transfection of mammalian cells.

Results: CDA resequencing revealed 17 polymorphisms, including one common nonsynonymous cSNP, 79 A>C (Lys27Gln). Recombinant Gln27 CDA had 66 ± 5.1% (mean ± SE) of the wild-type (WT) activity for gemcitabine but without a significant decrease in level of immunoreactive protein. The apparent K_m (397 ± 40 µmol/L) for the Gln27 allozyme was significantly higher than that for the WT (289 ± 20 µmol/L; P < 0.025). CDA 5'-flanking region reporter gene studies showed significant differences among 5'-flanking region haplotypes in their ability to drive transcription. There were 29 SNPs in DCTD, including one nonsynonymous cSNP, 172 A>G (Asn58Asp), in Caucasian American DNA. Recombinant Asp58 DCTD had 11 ± 1.4% of WT activity for gemcitabine monophosphate with a significantly elevated level of immunoreactive protein. No DCTD polymorphisms were observed in the initial 500 bp of the 5'-flanking region.

Conclusions: These results suggest that pharmacogenomic variation in the deamination of gemcitabine and its monophosphate might contribute to variation in therapeutic response to this antineoplastic agent.

This article has been cited by other articles:

				L. P. Jordheim, T. Nguyen-Dumont, X. Thomas, C. Dumontet, and S. V. Tavtigian Differential Allelic Expression in Leukoblast from Patients with Acute Myeloid Leukemia Suggests Genetic Regulation of CDA, DCK, NT5C2, NT5C3, and TP53 Drug Metab. Dispos., December 1, 2008; 36(12): 2419 - 2423. [Abstract] [Full Text] [PDF]

				S. A. Veltkamp, R. S. Jansen, S. Callies, D. Pluim, C. M. Visseren-Grul, H. Rosing, S. Kloeker-Rhoades, V. A.M. Andre, J. H. Beijnen, C. A. Slapak, et al. Oral Administration of Gemcitabine in Patients with Refractory Tumors: A Clinical and Pharmacologic Study Clin. Cancer Res., June 1, 2008; 14(11): 3477 - 3486. [Abstract] [Full Text] [PDF]

				C. Tibaldi, E. Giovannetti, E. Vasile, V. Mey, A. C. Laan, S. Nannizzi, R. Di Marsico, A. Antonuzzo, C. Orlandini, S. Ricciardi, et al. Correlation of CDA, ERCC1, and XPD Polymorphisms with Response and Survival in Gemcitabine/Cisplatin-Treated Advanced Non-Small Cell Lung Cancer Patients Clin. Cancer Res., March 15, 2008; 14(6): 1797 - 1803. [Abstract] [Full Text] [PDF]

				C. Mercier, A. Evrard, and J. Ciccolini Genotype-Based Methods for Anticipating Gemcitabine-Related Severe Toxicities May Lead to False-Negative Results J. Clin. Oncol., October 20, 2007; 25(30): 4855 - 4855. [Full Text] [PDF]

				N. Kaniwa, E. Sugiyama, S.-R. Kim, Y. Saito, J.-i. Sawada, J. Furuse, H. Ishii, T. Yoshida, H. Ueno, T. Okusaka, et al. In Reply J. Clin. Oncol., October 20, 2007; 25(30): 4855 - 4856. [Full Text] [PDF]

				Y. Mita, T. Ajiki, T. Kamigaki, T. Okazaki, H. Hori, H. Horiuchi, K. Hirata, T. Fujita, T. Fujimori, and Y. Kuroda Antitumor Effect of Gemcitabine on Orthotopically Inoculated Human Gallbladder Cancer Cells in Nude Mice Ann. Surg. Oncol., April 1, 2007; 14(4): 1374 - 1380. [Abstract] [Full Text] [PDF]

				E. Sugiyama, N. Kaniwa, S.-R. Kim, R. Kikura-Hanajiri, R. Hasegawa, K. Maekawa, Y. Saito, S. Ozawa, J.-i. Sawada, N. Kamatani, et al. Pharmacokinetics of Gemcitabine in Japanese Cancer Patients: The Impact of a Cytidine Deaminase Polymorphism J. Clin. Oncol., January 1, 2007; 25(1): 32 - 42. [Abstract] [Full Text] [PDF]