Glaysher, Sharon, Yiannakis, Dennis, Gabriel, Francis G., Johnson, Penny, Polak, Marta E., Knight, Louise A., Goldthorpe, Zoe, Peregrin, Katharine, Gyi, Mya, Modi, Paul, Rahamim, Joe, Smith, Mark E., Dr., Amer, Khalil, Addis, B. J. (Bruce J.), Poole, Matthew, Narayanan, Ajit, Gulliford, Tim J., Andreotti, Peter Eugene, 1951- and Cree, Ian A.. (2009) Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC). BMC Cancer, Vol.9 (No.1). p. 300. ISSN 1471-2407

Preview

Text WRAP_Cree_Resistance_gene_expression.pdf - Published Version Download (534Kb) | Preview

Abstract

Background NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors. Methods The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array™ following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue. Results There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents. Conclusion Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions:	Faculty of Medicine > Warwick Medical School > Reproductive Health
Library of Congress Subject Headings (LCSH):	Lungs -- Cancer -- Treatment, Drug resistance in cancer cells -- Genetic aspects
Journal or Publication Title:	BMC Cancer
Publisher:	BioMed Central Ltd.
ISSN:	1471-2407
Date:	27 August 2009
Volume:	Vol.9
Number:	No.1
Page Range:	p. 300
Identification Number:	10.1186/1471-2407-9-300
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	CanTech Ltd., Sanofi Aventis (Firm)
References:	1. Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, et al.: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000, 18(12):2354-2362. 2. Vogt U, Zaczek A, Klinke F, Granetzny A, Bielawski K, Falkiewicz B: p53 Gene status in relation to ex vivo chemosensitivity of non-small cell lung cancer. J Cancer Res Clin Oncol 2002, 128(3):141-147. 3. Kawamura M, Gika M, Abiko T, Inoue Y, Oyama T, Izumi Y, Kobayashi H, Kobayashi K: Clinical evaluation of chemosensitivity testing for patients with unresectable non-small cell lung cancer (NSCLC) using collagen gel droplet embedded culture drug sensitivity test (CD-DST). Cancer Chemother Pharmacol 2007, 59(4):507-513. 4. Inoue Y, Gika M, Abiko T, Oyama T, Saitoh Y, Yamazaki H, Nakamura M, Abe Y, Kawamura M, Kobayashi K: Bcl-2 overexpression enhances in vitro sensitivity against docetaxel in non-small cell lung cancer. Oncol Rep 2005, 13(2):259-264. 5. Vogt U, Striehn E, Bosse U, Klinke F, Falkiewicz B: Lack of squamous cell lung carcinoma in vitro chemosensitivity to various drug regimens in the adenosine triphosphate cell viability chemosensitivity assay. Acta Biochim Pol 1999, 46(2):299-302. 6. Kurbacher CM, Cree IA, Bruckner HW, Brenne U, Kurbacher JA, Muller K, Ackermann T, Gilster TJ, Wilhelm LM, Engel H, et al.: Use of an ex vivo ATP luminescence assay to direct chemotherapy for recurrent ovarian cancer. Anticancer Drugs 1998, 9(1):51-57. 7. Konecny G, Crohns C, Pegram M, Felber M, Lude S, Kurbacher C, Cree IA, Hepp H, Untch M: Correlation of drug response with the ATP tumorchemosensitivity assay in primary FIGO stage III ovarian cancer. Gynecol Oncol 2000, 77(2):258-263. 8. Fiebig HH, Maier A, Burger AM: Clonogenic assay with established human tumour xenografts: correlation of in vitro to in vivo activity as a basis for anticancer drug discovery. Eur J Cancer 2004, 40(6):802-820. 9. Wigle DA, Jurisica I, Radulovich N, Pintilie M, Rossant J, Liu N, Lu C, Woodgett J, Seiden I, Johnston M, et al.: Molecular profiling of non-small cell lung cancer and correlation with disease-free survival. Cancer Res 2002, 62(11):3005-3008. 10. Kikuchi T, Daigo Y, Katagiri T, Tsunoda T, Okada K, Kakiuchi S, Zembutsu H, Furukawa Y, Kawamura M, Kobayashi K, et al.: Expression profiles of non-small cell lung cancers on cDNA microarrays: identification of genes for prediction of lymph-node metastasis and sensitivity to anti-cancer drugs. Oncogene 2003, 22(14):2192-2205. 11. Felip E, Stahel RA, Pavlidis N: ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of nonsmall- cell lung cancer (NSCLC). Ann Oncol 2005, 16(Suppl 1):i28-29. 12. Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker S Jr, Olak J, Stover D, Strawn JR, Turrisi AT, et al.: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 2004, 22(2):330-353. 13. Cree IA, Knight L, Di Nicolantonio F, Sharma S, Gulliford T: Chemosensitization of solid tumors by modulation of resistance mechanisms. Curr Opin Investig Drugs 2002, 3(4):634-640. 14. Cree IA, Knight L, Di Nicolantonio F, Sharma S, Gulliford T: Chemosensitization of solid tumor cells by alteration of their susceptibility to apoptosis. Curr Opin Investig Drugs 2002, 3(4):641-647. 15. Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, et al.: DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006, 355(10):983-991. 16. Simon G, Sharma A, Li X, Hazelton T, Walsh F, Williams C, Chiappori A, Haura E, Tanvetyanon T, Antonia S, et al.: Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. J Clin Oncol 2007, 25(19):2741-2746. 17. Brown R, Hirst GL, Gallagher WM, McIlwrath AJ, Margison GP, Zee AG van der, Anthoney DA: hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents. Oncogene 1997, 15(1):45-52. 18. Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R: Reversal of drug resistance in human tumor xenografts by 2'-deoxy-5- azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res 2000, 60(21):6039-6044. 19. Fedier A, Fink D: Mutations in DNA mismatch repair genes: implications for DNA damage signaling and drug sensitivity (review). Int J Oncol 2004, 24(4):1039-1047. 20. Rabik CA, Njoku MC, Dolan ME: Inactivation of O6-alkylguanine DNA alkyltransferase as a means to enhance chemotherapy. Cancer Treat Rev 2006, 32(4):261-276. 21. Young LC, Campling BG, Cole SP, Deeley RG, Gerlach JH: Multidrug resistance proteins MRP3, MRP1, and MRP2 in lung cancer: correlation of protein levels with drug response and messenger RNA levels. Clin Cancer Res 2001, 7(6):1798-1804. 22. Cummings M, Higginbottom K, McGurk CJ, Wong OG, Koberle B, Oliver RT, Masters JR: XPA versus ERCC1 as chemosensitising agents to cisplatin and mitomycin C in prostate cancer cells: role of ERCC1 in homologous recombination repair. Biochem Pharmacol 2006, 72(2):166-175. 23. Siddik ZH: Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003, 22(47):7265-7279. 24. Mini E, Nobili S, Caciagli B, Landini I, Mazzei T: Cellular pharmacology of gemcitabine. Ann Oncol 2006, 17(Suppl 5):v7-v12. 25. Seve P, Mackey JR, Isaac S, Tredan O, Souquet PJ, Perol M, Cass C, Dumontet C: cN-II expression predicts survival in patients receiving gemcitabine for advanced non-small cell lung cancer. Lung Cancer 2005, 49(3):363-370. 26. Bepler G, Kusmartseva I, Sharma S, Gautam A, Cantor A, Sharma A, Simon G: RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol 2006, 24(29):4731-4737. 27. Wachters FM, Wong LS, Timens W, Kampinga HH, Groen HJ: ERCC1, hRad51, and BRCA1 protein expression in relation to tumour response and survival of stage III/IV NSCLC patients treated with chemotherapy. Lung Cancer 2005, 50(2):211-219. 28. Maring JG, Groen HJ, Wachters FM, Uges DR, de Vries EG: Genetic factors influencing pyrimidine-antagonist chemotherapy. Pharmacogenomics J 2005, 5(4):226-243. 29. Zhao J, Kim JE, Reed E, Li QQ: Molecular mechanism of antitumor activity of taxanes in lung cancer (Review). Int J Oncol 2005, 27(1):247-256. 30. Yoshino T, Shiina H, Urakami S, Kikuno N, Yoneda T, Shigeno K, Igawa M: Bcl-2 expression as a predictive marker of hormonerefractory prostate cancer treated with taxane-based chemotherapy. Clin Cancer Res 2006, 12(20 Pt 1):6116-6124. 31. Smith JA, Gaikwad A, Ramondetta LM, Wolf JK, Brown J: Determination of the mechanism of gemcitabine modulation of cisplatin drug resistance in panel of human endometrial cancer cell lines. Gynecol Oncol 2006, 103(2):518-522. 32. Rosell R, Cobo M, Isla D, Camps C, Massuti B: Pharmacogenomics and gemcitabine. Ann Oncol 2006, 17(Suppl 5):v13-v16. 33. Andreotti PE, Cree IA, Kurbacher CM, Hartmann DM, Linder D, Harel G, Gleiberman I, Caruso PA, Ricks SH, Untch M, et al.: Chemosensitivity testing of human tumors using a microplate adenosine triphosphate luminescence assay: clinical correlation for cisplatin resistance of ovarian carcinoma. Cancer Res 1995, 55(22):5276-5282. 34. Cree IA: Luminescence-based cell viability testing. Methods in Molecular Biology 1998, 1998(102):169-177. 35. Hunter EM, Sutherland LA, Cree IA, Dewar JA, Preece PE, Wood RA, Linder D, Andreotti PE: Heterogeneity of chemosensitivity in human breast carcinoma: use of an adenosine triphosphate (ATP) chemiluminescence assay. Eur J Surg Oncol 1993, 19(3):242-249. 36. Giovannetti E, Del Tacca M, Mey V, Funel N, Nannizzi S, Ricci S, Orlandini C, Boggi U, Campani D, Del Chiaro M, et al.: Transcription analysis of human equilibrative nucleoside transporter- 1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res 2006, 66(7):3928-3935. 37. van Moorsel CJ, Pinedo HM, Smid K, Comijn EM, Voorn DA, Veerman G, Lakerveld B, Vijgh WJ Van der, Giaccone G, Postmus PE, et al.: Schedule-dependent pharmacodynamic effects of gemcitabine and cisplatin in mice bearing Lewis lung murine nonsmall cell lung tumours. Eur J Cancer 2000, 36(18):2420-2429. 38. Anderson H, Hopwood P, Stephens RJ, Thatcher N, Cottier B, Nicholson M, Milroy R, Maughan TS, Falk SJ, Bond MG, et al.: Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer – a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-Small Cell Lung Cancer. Br J Cancer 2000, 83(4):447-453. 39. Peters GJ, Wilt CL van der, van Moorsel CJ, Kroep JR, Bergman AM, Ackland SP: Basis for effective combination cancer chemotherapy with antimetabolites. Pharmacol Ther 2000, 87(2– 3):227-253.
URI:	http://wrap.warwick.ac.uk/id/eprint/49846

Request changes to a record

Actions (login required)

View Item