This Article Full Text Full Text (PDF) 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 Davidson, J. D. Articles by Slapak, C. A. Search for Related Content PubMed PubMed Citation Articles by Davidson, J. D. Articles by Slapak, C. A.

An Increase in the Expression of Ribonucleotide Reductase Large Subunit 1 Is Associated with Gemcitabine Resistance in Non-Small Cell Lung Cancer Cell Lines

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana

The mechanisms of resistance to the antimetabolite gemcitabine in non-small cell lung cancer have not been extensively evaluated. In this study, we report the generation of two gemcitabine-selected non-small cell lung cancer cell lines, H358-G200 and H460-G400. Expression profiling results indicated that there was evidence for changes in the expression of 134 genes in H358-G200 cells compared with its parental line, whereas H460-G400 cells exhibited 233 genes that appeared to be under- or overexpressed compared with H460 cells. However, only the increased expression of ribonucleotide reductase subunit 1 (RRM1), which appeared in both resistant cell lines, met predefined analysis criteria for genes to investigate further. Quantitative PCR analysis demonstrated H358-G200 cells had a greater than 125-fold increase in RRM1 RNA expression. Western blot analysis confirmed high levels of RRM1 protein in this line compared with the gemcitabine-sensitive parent. No significant change in the expression of RRM2 was observed in either cell line, although both gemcitabine-resistant cell lines had an approximate 3-fold increase in p53R2 protein. A partial revertant of H358-G200 cells had reduced levels of RRM1 protein (compared with G200 cells), without observed changes in RRM2 or p53R2. In vitro analyses of ribonucleotide reductase activity demonstrated that despite high levels of RRM1 protein, ribonucleotide reductase activity was not increased in H358-G200 cells when compared with parental cells. The cDNA encoding RRM1 from H358-G200 cells was cloned and sequenced but did not reveal the presence of any mutations. The results from this study indicate that the level of RRM1 may affect gemcitabine response. Furthermore, RRM1 may serve as a biomarker for gemcitabine response.

This article has been cited by other articles:

				X. Wu and M. Huang Dif1 Controls Subcellular Localization of Ribonucleotide Reductase by Mediating Nuclear Import of the R2 Subunit Mol. Cell. Biol., December 1, 2008; 28(23): 7156 - 7167. [Abstract] [Full Text] [PDF]

				J. D. Fowler, J. A. Brown, K. A. Johnson, and Z. Suo Kinetic Investigation of the Inhibitory Effect of Gemcitabine on DNA Polymerization Catalyzed by Human Mitochondrial DNA Polymerase J. Biol. Chem., May 30, 2008; 283(22): 15339 - 15348. [Abstract] [Full Text] [PDF]

				S.-O. Kim, J.-Y. Jeong, M.-R. Kim, H.-J. Cho, J.-Y. Ju, Y.-S. Kwon, I.-J. Oh, K.-S. Kim, Y.-I. Kim, S.-C. Lim, et al. Efficacy of Gemcitabine in Patients with Non-Small Cell Lung Cancer According to Promoter Polymorphisms of the Ribonucleotide Reductase M1 Gene Clin. Cancer Res., May 15, 2008; 14(10): 3083 - 3088. [Abstract] [Full Text] [PDF]

				J. Cai, V. L. Damaraju, N. Groulx, D. Mowles, Y. Peng, M. J. Robins, C. E. Cass, and P. Gros Two Distinct Molecular Mechanisms Underlying Cytarabine Resistance in Human Leukemic Cells Cancer Res., April 1, 2008; 68(7): 2349 - 2357. [Abstract] [Full Text] [PDF]

				G. Bepler Genes Predictive of Chemotherapeutic Efficacy in Non-small Cell Lung Cancer ASCO Educational Book, January 1, 2008; 2008(1): 350 - 352. [Abstract] [Full Text] [PDF]

				J. Wang, G. J. S. Lohman, and J. Stubbe Enhanced subunit interactions with gemcitabine-5'-diphosphate inhibit ribonucleotide reductases PNAS, September 4, 2007; 104(36): 14324 - 14329. [Abstract] [Full Text] [PDF]

				G. Simon, A. Sharma, X. Li, T. Hazelton, F. Walsh, C. Williams, A. Chiappori, E. Haura, T. Tanvetyanon, S. Antonia, et al. Feasibility and Efficacy of Molecular Analysis-Directed Individualized Therapy in Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., July 1, 2007; 25(19): 2741 - 2746. [Abstract] [Full Text] [PDF]

				S. Y. Rha, H. C. Jeung, Y. H. Choi, W. I. Yang, J. H. Yoo, B. S. Kim, J. K. Roh, and H. C. Chung An Association Between RRM1 Haplotype and Gemcitabine-Induced Neutropenia in Breast Cancer Patients Oncologist, June 1, 2007; 12(6): 622 - 630. [Abstract] [Full Text] [PDF]

				P. Tooker, W.-C. Yen, S.-C. Ng, A. Negro-Vilar, and T. W. Hermann Bexarotene (LGD1069, Targretin), a Selective Retinoid X Receptor Agonist, Prevents and Reverses Gemcitabine Resistance in NSCLC Cells by Modulating Gene Amplification Cancer Res., May 1, 2007; 67(9): 4425 - 4433. [Abstract] [Full Text] [PDF]

				J Bellmunt, L Paz-Ares, M Cuello, F. Cecere, S Albiol, V Guillem, E Gallardo, J Carles, P Mendez, J. de la Cruz, et al. Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy Ann. Onc., March 1, 2007; 18(3): 522 - 528. [Abstract] [Full Text] [PDF]

				Z. Zheng, T. Chen, X. Li, E. Haura, A. Sharma, and G. Bepler DNA Synthesis and Repair Genes RRM1 and ERCC1 in Lung Cancer N. Engl. J. Med., February 22, 2007; 356(8): 800 - 808. [Abstract] [Full Text] [PDF]

				P Ceppi, M Volante, S Novello, I Rapa, K. Danenberg, P. Danenberg, A Cambieri, G Selvaggi, S Saviozzi, R Calogero, et al. ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine Ann. Onc., December 1, 2006; 17(12): 1818 - 1825. [Abstract] [Full Text] [PDF]

				G. Bepler, I. Kusmartseva, S. Sharma, A. Gautam, A. Cantor, A. Sharma, and G. Simon RRM1 Modulated In Vitro and In Vivo Efficacy of Gemcitabine and Platinum in Non-Small-Cell Lung Cancer J. Clin. Oncol., October 10, 2006; 24(29): 4731 - 4737. [Abstract] [Full Text] [PDF]

				T. Oguri, H. Achiwa, S. Sato, Y. Bessho, Y. Takano, M. Miyazaki, H. Muramatsu, H. Maeda, T. Niimi, and R. Ueda The determinants of sensitivity and acquired resistance to gemcitabine differ in non-small cell lung cancer: a role of ABCC5 in gemcitabine sensitivity. Mol. Cancer Ther., July 1, 2006; 5(7): 1800 - 1806. [Abstract] [Full Text] [PDF]

				E. Giovannetti, V. Mey, S. Nannizzi, G. Pasqualetti, M. Del Tacca, and R. Danesi Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer. Mol. Cancer Ther., June 1, 2006; 5(6): 1387 - 1395. [Abstract] [Full Text] [PDF]

				E. Giovannetti, M. Del Tacca, V. Mey, N. Funel, S. Nannizzi, S. Ricci, C. Orlandini, U. Boggi, D. Campani, M. Del Chiaro, et al. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res., April 1, 2006; 66(7): 3928 - 3935. [Abstract] [Full Text] [PDF]

				M. A. van de Wiel, J. L. Costa, K. Smid, C. B.M. Oudejans, A. M. Bergman, G. A. Meijer, G. J. Peters, and B. Ylstra Expression Microarray Analysis and Oligo Array Comparative Genomic Hybridization of Acquired Gemcitabine Resistance in Mouse Colon Reveals Selection for Chromosomal Aberrations Cancer Res., November 15, 2005; 65(22): 10208 - 10213. [Abstract] [Full Text] [PDF]

				A. M. Bergman, P. P. Eijk, V. W.T. Ruiz van Haperen, K. Smid, G. Veerman, I. Hubeek, P. van den IJssel, B. Ylstra, and G. J. Peters In vivo Induction of Resistance to Gemcitabine Results in Increased Expression of Ribonucleotide Reductase Subunit M1 as the Major Determinant Cancer Res., October 15, 2005; 65(20): 9510 - 9516. [Abstract] [Full Text] [PDF]

				L. P. Jordheim, O. Guittet, M. Lepoivre, C. M. Galmarini, and C. Dumontet Increased expression of the large subunit of ribonucleotide reductase is involved in resistance to gemcitabine in human mammary adenocarcinoma cells Mol. Cancer Ther., August 1, 2005; 4(8): 1268 - 1276. [Abstract] [Full Text] [PDF]

				M. Akada, T. Crnogorac-Jurcevic, S. Lattimore, P. Mahon, R. Lopes, M. Sunamura, S. Matsuno, and N. R. Lemoine Intrinsic Chemoresistance to Gemcitabine Is Associated with Decreased Expression of BNIP3 in Pancreatic Cancer Clin. Cancer Res., April 15, 2005; 11(8): 3094 - 3101. [Abstract] [Full Text] [PDF]