Lung Cancer
Volume 70, Issue 2 , Pages 205-210 , November 2010

The immunohistochemical overexpression of ribonucleotide reductase regulatory subunit M1 (RRM1) protein is a predictor of shorter survival to gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC)

  • Jae Jin Lee

      Affiliations

    • Department of Medical Oncology & Hematology, East-West Neo Medical Center, Kyung Hee University, #149, Sangil-dong, Gangdong-gu, 134-727 Seoul, Republic of Korea
    • Corresponding Author InformationCorresponding author. Tel.: +82 2 440 6123; fax: +82 2 440 6295.
  • ,
  • Chi Hoon Maeng

      Affiliations

    • Department of Medical Oncology & Hematology, Kyung Hee Medical Center, Kyung Hee University, Seoul, Republic of Korea
  • ,
  • Seon Kyung Baek

      Affiliations

    • Department of Medical Oncology & Hematology, Kyung Hee Medical Center, Kyung Hee University, Seoul, Republic of Korea
  • ,
  • Gou Young Kim

      Affiliations

    • Department of Anatomical Pathology, East-West Neo Medical Center, Kyung Hee University, Seoul, Republic of Korea
  • ,
  • Jee-Hong Yoo

      Affiliations

    • Department of Pulmonology, East-West Neo Medical Center, Kyung Hee University, Seoul, Republic of Korea
  • ,
  • Cheon Woong Choi

      Affiliations

    • Department of Pulmonology, East-West Neo Medical Center, Kyung Hee University, Seoul, Republic of Korea
  • ,
  • Yee Hyung Kim

      Affiliations

    • Department of Pulmonology, East-West Neo Medical Center, Kyung Hee University, Seoul, Republic of Korea
  • ,
  • Young-Tae Kwak

      Affiliations

    • Department of Thoracic & Cardiovascular Surgery, East-West Neo Medical Center, Kyung Hee University, Seoul, Republic of Korea
  • ,
  • Dae-Hyun Kim

      Affiliations

    • Department of Thoracic & Cardiovascular Surgery, East-West Neo Medical Center, Kyung Hee University, Seoul, Republic of Korea
  • ,
  • Young Kyung Lee

      Affiliations

    • Department of Radiology, East-West Neo Medical Center, Kyung Hee University, Seoul, Republic of Korea
  • ,
  • Jung Bo Kim

      Affiliations

    • Department of Pharmacy, East-West Neo Medical Center, Kyung Hee University, Seoul, Republic of Korea
  • ,
  • Si-Young Kim

      Affiliations

    • Department of Medical Oncology & Hematology, Kyung Hee Medical Center, Kyung Hee University, Seoul, Republic of Korea

Received 13 August 2009 ,Revised 3 November 2009 ,Accepted 9 February 2010.

References 

  1. Ruckdeschel JC, Schwartz AG, Bepler G. Cancer of the lung: NSCLC and SCLC. In:  Abeloff MD,  Armitage JO,  Niederhuber JE,  Kastan MB,  McKenna WG editor. Clinical oncology. 3rd ed.. Philadelphia: Elsevier; 2004;p. 1649–1743
  2. Korea National Statistical Office. Annual report on the cause of death statistics, Seoul, Republic of Korea; 2006.
  3. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92–98
  4. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009;27:1227–1234
  5. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184–2191
  6. Bepler G, Gautam A, McIntyre LM, Beck AF, Chervinsky DS, Kim YC, et al. Prognostic significance of molecular genetic aberrations on chromosome segment 11p15.5 in non-small-cell lung cancer. J Clin Oncol. 2002;20:1353–1360
  7. Pitterle DM, Kim YC, Jolicoeur EM, Cao Y, O’Briant KC, Bepler G. Lung cancer and the human gene for ribonucleotide reductase subunit M1 (RRM1). Mamm Genome. 1999;10:916–922
  8. Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R, Gandhi V. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol. 1995;22:3–10
  9. Kim SO, Jeong JY, Kim MR, Cho HJ, Ju JY, Kwon YS, 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. 2008;14:3083–3088
  10. Ceppi P, Volante M, Novello S, Rapa I, Danenberg KD, Danenberg PV, 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 Oncol. 2006;17:1818–1825
  11. Rosell R, Danenberg KD, Alberola V, Bepler G, Sanchez JJ, Camps C, et al. Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res. 2004;10:1318–1325
  12. Souglakos J, Boukovinas I, Taron M, Mendez P, Mavroudis D, Tripaki M, et al. Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel/gemcitabine. Br J Cancer. 2008;98:1710–1715
  13. Giovannetti E, Del Tacca M, Mey V, Funel N, Nannizzi S, Ricci S, et al. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res. 2006;66:3928–3935
  14. Gautam A, Li ZR, Bepler G. RRM1-induced metastasis suppression through PTEN-regulated pathways. Oncogene. 2003;22:2135–2142
  15. Fan H, Huang A, Villegas C, Wright JA. The R1 component of mammalian ribonucleotide reductase has malignancy-suppressing activity as demonstrated by gene transfer experiments. Proc Natl Acad Sci U S A. 1997;94:13181–13186
  16. Gautam A, Bepler G. Suppression of lung tumor formation by the regulatory subunit of ribonucleotide reductase. Cancer Res. 2006;66:6497–6502
  17. Zheng Z, Chen T, Li X, Haura E, Sharma A, Bepler G. DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med. 2007;356:800–808
  18. Rosell R, Felip E, Taron M, Majo J, Mendez P, Sanchez-Ronco M, 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. Clin Cancer Res. 2004;10:4215s–4219s
  19. Bepler G, Sharma S, Cantor A, Gautam A, Haura E, Simon G, et al. RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer. J Clin Oncol. 2004;22:1878–1885
  20. Davidson JD, Ma L, Flagella M, Geeganage S, Gelbert LM, Slapak CA. An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Cancer Res. 2004;64:3761–3766
  21. Bepler G, Kusmartseva I, Sharma S, Gautam A, Cantor A, Sharma A, et al. RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol. 2006;24:4731–4737
  22. World Health Organization . WHO handbook for reporting results of cancer treatment. WHO offset publication no. 48. Geneva: World Health Organization; 1979;
  23. Kaplan ES, Meier P. Non-parametric estimation from incomplete observation. J Am Stat Assoc. 1958;53:457–481
  24. Abratt RP, Hart GJ. 10-year update on chemotherapy for non-small cell lung cancer. Ann Oncol. 2006;17(Suppl. 5):v33–v36
  25. Le Chevalier T, Scagliotti G, Natale R, Danson S, Rosell R, Stahel R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer. 2005;47:69–80
  26. Lee DH, Han JY, Lee HG, Lee JJ, Lee EK, Kim HY, et al. Gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in never-smokers. Clin Cancer Res. 2005;11:3032–3037
  27. Olaussen KA, Dunant A, Fouret P, Brambilla E, André F, Haddad V, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006;355:983–991
  28. Lord RV, Brabender J, Gandara D, Alberola V, Camps C, Domine M, et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res. 2002;8:2286–2291
  29. Wang X, Zhao J, Yang L, Mao L, An T, Bai H, et al. Positive expression of ERCC1 predicts a poorer platinum-based treatment outcome in Chinese patients with advanced non-small-cell lung cancer. Med Oncol. 2009;[epub ahead of print]
  30. Ohtaka K, Kohya N, Sato K, Kitajima Y, Ide T, Mitsuno M, et al. Ribonucleotide reductase subunit M1 is a possible chemoresistance marker to gemcitabine in biliary tract carcinoma. Oncol Rep. 2008;20:279–286
  31. Akita H, Zheng Z, Takeda Y, Kim C, Kittaka N, Kobayashi S, et al. Significance of RRM1 and ERCC1 expression in resectable pancreatic adenocarcinoma. Oncogene. 2009;28:2903–2909
  32. Sauter G, Lee J, Bartlett JM, Slamon DJ, Press MF . Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations. J Clin Oncol. 2009;27:1323–1333
  33. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22:1589–1597
  34. Ceppi P, Volante M, Saviozzi S, Rapa I, Novello S, Cambieri A, et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer. 2006;107:1589–1596

PII: S0169-5002(10)00070-X

doi: 10.1016/j.lungcan.2010.02.005

Lung Cancer
Volume 70, Issue 2 , Pages 205-210 , November 2010