Aim. To evaluate the predictive value of RRM1, ERCCl, and BRCA1 expression in Chinese NSCLC patients treated with gemcitabine and cisplatin. Methods. Real-time fluorescent quantitative PCR was used to determine the RRM1, ERCC1, and BRCA1 mRNA expression levels of peripheral blood in late-stage NSCLC patients. The relationship between peripheral blood and mRNA expression in tumor tissues was analyzed further. Results. In terms of the tumor susceptibility to chemotherapy, the response rate in the low-RRM1-expression group was significantly greater than in the high-expression group (52.9%？versus 5.9%, test, ). Subjects with low peripheral blood RRM1 expression survived longer than those with high RRM1 expression (15.5？versus 12.0 months, logrank 3.980, ). Linear correlations were observed between peripheral blood and tumor tissue expression levels for RRM1 ) and BRCA1 ). Conclusion. Our study demonstrates increased survival and superior efficacy of gemcitabine and cisplatin combination chemotherapy in the treatment of NSCLC patients with low peripheral blood RRM1 expression. The linear correlations of the relative expression of mRNA were observed between peripheral blood and tumor tissue expression levels for RRM1 and BRCA1. RRM1 gene expression may contribute to chemotherapy sensitivity and may be an indicator of survival. It was significant to individual chemotherapy of patients with advanced NSCLC who do not have sufficient tumor tissue. 1. Introduction In recent years, research has focused on abnormal DNA repair and drug resistance for individualized treatment of lung cancer. Ribonucleotide reductase (RR) catalyzes the formation of deoxyribonucleotides from ribonucleotides. It plays a key role in repairing DNA and it is also an important rate-limiting enzyme during DNA synthesis. The M1 subunit of RR (RRM1) is the nucleotide-binding site, which controls substrate specificity and enzyme activity. RRM1 also is the binding site for chemotherapy drugs such as gemcitabine and other nucleoside analogues [1]. Preclinical studies have shown that patients with low tumor tissue RRM1 expression had greater median length of disease progression and median survival time than did patients with high tumor tissue RRM1 expression. RRM1 expression level is associated with gemcitabine resistance in tumor cells [2, 3]. Therefore, RRM1 expression level is an important benchmark for the selection of patients for gemcitabine chemotherapy. The excision repair cross complementation 1 gene (ERCCl) is involved in DNA damage repair and excision caused by cisplatin drugs. In recent
References
[1]
Y. F. Jing and Y. Wang, “The development of predicting the lung cancer prognosis and resistance to gemcitabine by the expression level of RRM1,” Journal of Clinical Pulmonary Medicine, vol. 13, pp. 1268–1270, 2008.
[2]
R. Rosell, K. D. Danenberg, V. Alberola et al., “Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients,” Clinical Cancer Research, vol. 10, no. 4, pp. 1318–1325, 2004.
[3]
R. Rosell, E. Felip, M. Taron et al., “Gene expression as a predictive marker of outcome in stage IIB-IIIA-IIIB non-small cell lung cancer after induction gemcitabine-based chemotherapy followed by resectional surgery,” Clinical Cancer Research, vol. 10, no. 12, pp. 4215–4219, 2004.
[4]
K. A. Olaussen, A. Dunant, P. Fouret et al., “DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy,” The New England Journal of Medicine, vol. 355, no. 10, pp. 983–991, 2006.
[5]
K. A. Olaussen, P. Fouret, and G. Kroemer, “ERCC1-specific immunostaining in non-small-cell lung cancer,” The New England Journal of Medicine, vol. 357, no. 15, pp. 1559–1561, 2007.
[6]
M. Taron, R. Rosell, E. Felip et al., “BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer,” Human Molecular Genetics, vol. 13, no. 20, pp. 2443–2449, 2004.
[7]
R. Rosell, M. Skrzypski, E. Jassem et al., “BRCA1: a novel prognostic factor in resected non-small-cell lung cancer,” PLoS ONE, vol. 2, no. 11, article e1129, 2007.
[8]
L.-R. Wang, G.-B. Zhang, J. Chen et al., “RRM1 gene expression in peripheral blood is predictive of shorter survival in Chinese patients with advanced non-small-cell lung cancer treated by gemcitabine and platinum,” Journal of Zhejiang University B, vol. 12, no. 3, pp. 174–179, 2011.
[9]
L. R. Wang, M. Z. Huang, G. B. Zhang, N. Xu, and X. H. Wu, “Phase II study of gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer,” Cancer Chemotherapy and Pharmacology, vol. 60, no. 4, pp. 601–607, 2007.
[10]
L. R. Wang, X. H. Wu, M. Z. Huang, J. Cai, N. Xu, and J. Liu, “The efficacy and relationship between peak concentration and toxicity profile of fixed-dose-rate gemcitabine plus carboplatin in patients with advanced non-small-cell lung cancer,” Cancer Chemotherapy and Pharmacology, vol. 60, no. 2, pp. 211–218, 2007.
[11]
R. Rosell, K. D. Danenberg, V. Alberola et al., “Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients,” Clinical Cancer Research, vol. 10, no. 4, pp. 1318–1325, 2004.
[12]
P. Ceppi, M. Volante, S. Novello 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,” Annals of Oncology, vol. 17, no. 12, pp. 1818–1825, 2006.
[13]
A. M. Bergman, P. P. Eijk, V. W. T. Ruiz Van Haperen et al., “In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant,” Cancer Research, vol. 65, no. 20, pp. 9510–9516, 2005.
[14]
G. Bepler, I. Kusmartseva, S. Sharma et al., “RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer,” Journal of Clinical Oncology, vol. 24, no. 29, pp. 4731–4737, 2006.
[15]
M. Taron, R. Rosell, E. Felip et al., “BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer,” Human Molecular Genetics, vol. 13, no. 20, pp. 2443–2449, 2004.
