Abstract
The activity of the following drugs was investigated in two established NSCLC cell lines: docetaxel, gemcitabine, vinorelbine, paclitaxel, doxorubicin (0.01, 0.1, 1 μg ml–1), cisplatin, ifosfamide (1, 2, 3 μg ml–1) and carboplatin (2, 4, 6 μg ml–1). The cytotoxic activity was evaluated by the sulphorhodamine B assay. The two most active drugs, docetaxel and gemcitabine, used singly and in association, were investigated as a function of treatment schedule. The sequence docetaxel→gemcitabine produced only a weak synergistic interaction in RAL but a strong synergism in CAEP cells. The synergistic interaction increased in both cell lines after a 48-h washout between the drug administrations. Flow cytometric analysis showed that in docetaxel→gemcitabine sequence, docetaxel produced a block in G2/M phase and, after 48 h, provided gemcitabine with a large fraction of recovered synchronized cells in the G1/S boundary, which is the specific target phase for gemcitabine. Conversely, simultaneous treatment induced an antagonistic effect in both cell lines, and the sequential scheme gemcitabine→docetaxel produced a weak synergistic effect only in RAL cells. Moreover, the synergistic interaction disappeared when washout periods of 24 or 48 h between two drug administrations were adopted. The synergistic activity of docetaxel→ 48-h washout→gemcitabine was confirmed in 11 of 14 primary cultures, which represents an important means of validating experimental results before translating them into clinical practice.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Amadori, D, Frassineti, GL, Zoli, W, Milandri, C, Tienghi, A, Ravaioli, A, Gentile, A & Salzano, E (1996) A phase I/II study of sequential doxorubicin and paclitaxel treatment of advanced breast cancer. Semin Oncol 23 (suppl 11) S16–S22.
Amadori, D, Frassineti, GL, De Matteis, A, Mustacchi, G, Santoro, A, Cariello, S, Ferrari, M, Nascinben, O, Nanni, O, Lombardi, A, Scarpi, E & Zoli, W (1998) Modulating effect of lonidamine on response to doxorubicin in metastatic breast cancer patients: results from a multicenter prospective randomized trial. Breast Cancer Res Treat 49: 209–217.
Belani, CP (1998) Single agents in the second-line treatment of non-small cell lung cancer. Semin Oncol 25 (suppl 8) S10–S14.
Boyer, MJ (1998) New chemotherapeutic agents in the treatment of non-small cell lung cancer: the Australian experience. Chest 113 (suppl 1) S24–S27.
Crino, L, Mosconi, AM, Scagliotti, G, De Marinis, F, Darwish, S, Calandri, C, Adamo, V, Scarcella, L, Pucci, F & Tonato, M (1997) Salvage therapy with gemcitabine (GEM) in pretreated, advanced non-small cell lung cancer (NSCLC). Proc Annu Meet Soc Clin Oncol 16: 1603
Citro, G, Cucco, C, Verdiana, A & Zupi, G (1991) Reversal of adriamycin resistance by lonidamine in a human breast cancer cell line. Br J Cancer 64: 534–536.
Cortes-Funes, H, Martin, C, Abrat, R & Lund, B (1997) Safety profile of gemcitabine, a novel anticancer agent, in non-small cell lung cancer. Anticancer Drugs 8: 582–587.
De Lena, M, Lorusso, V, Bottalico, C, Brandi, M, De Mitrio, A, Catino, A, Guida, M, Latorre, A, Leone, B, Vallejo, C & Gargano, G (1997) Revertant and potentiating activity of lonidamine in patients with ovarian cancer previously treated with platinum. J Clin Oncol 15: 3208–3213.
Dogliotti, L, Berruti, A, Buniva, T, Zola, P, Bau, MG, Farris, A, Sarobba, MG, Bottini, A, Alquati, P, Deltetto, F, Gosso, P, Monzeglio, C, Moro, G, Sussio, M & Perroni, D (1996) Lonidamine significantly increases the activity of epirubicin in patients with advanced breast cancer: results from a multicenter prospective randomized trial. J Clin Oncol 14: 1165–1172.
Drewinko, B, Loo, TL, Brown, B, Gottlieb, JA & Freireich, EJ (1976) Combination chemotherapy in vitro with adriamycin. Observations of additive, antagonistic and synergistic effects when used in two-drug combinations on cultured human lymphoma cells. Cancer Biochem Biophys 1: 187–195.
Feigal, EG, Christian, M & Cheson, B (1993) New chemotherapeutic agents in non-small cell lung cancer. Semin Oncol 20: 185–201.
Fischel, JL, Etienne, MC, Formento, P & Milano, G (1998) Search for the optimal schedule for the oxaliplatin/5-fluoruracil association modulated or not by folinic acid: preclinical data. Clin Cancer Res 4: 2529–2535.
Frassineti, GL, Zoli, W, Silvestro, L, Serra, P, Milandri, C, Tienghi, A, Gianni, L, Gentile, A, Salzano, E & Amadori, D (1997) Paclitaxel plus doxorubicin in breast cancer: an Italian expeirence. Semin Oncol 24: (suppl 17) S19–S25.
Gasperi-Campani, A, Roncuzzi, L, Ricotti, L, Lenzi, L, Gruppioni, R, Sensi, A, Zini, M, Zoli, W & Amadori, D (1998) Molecular and biological features of two new human cell lines from squamous and adenocarcinoma of the lung. Cancer Gen Cytogen 107: 11–20.
Georgoulias, V, Kourousis, C, Kakolyris, S, Androulakis, N, Dimopoulos, MA, Papadakis, E, Kotsakis, T, Vardakis, N, Kalbakis, K, Meramveliotakis, N & Hatzidaki, D (1997a) Second-line treatment of advanced non-small cell lung cancer with paclitaxel and gemcitabine: a preliminary report on an active regimen. Semin Oncol 24 (suppl 12): S61–S66.
Georgoulias, V, Kourousis, C, Androulakis, N, Kakolyris, S, Dimopoulos, MA, Bouros, D, Papadimitriou, C, Hatzakis, K, Heras, P, Kalbakis, K, Kotsakis, T, Vardakis, N, Meramveliotakis, N & Hatzidaki, D (1997b) Docetaxel (Taxotere) and gemcitabine in the treatment of non-small cell lung cancer: preliminary results. Semin Oncol 24 (suppl 14): S22–S25.
Georgoulias, V, Kourousis, C, Androulakis, N, Kakolyris, S, Dimopoulos, MA, Papadakis, E, Bouros, D, Apostolopaulou, F, Papadimitriou, C, Angelidou, A, Hatzakis, K, Kalbakis, K, Kotsakis, T, Vardakis, N & Vlachonicolis, J (1999) Front-line treatment of advanced non-small-cell lung cancer with docetaxel and gemcitabine: a multicenter phase II trial. J Clin Oncol 17: 914–920.
Hahn, SM, Liebman, JE, Cook, J, Fisher, J, Goldspiel, B, Venzon, D, Mitchell, JB & Kaupfman, D (1993) Taxol in combination with doxorubicin or etoposide. Cancer 72: 2705–2711.
Hertel, LW, Boder, GB, Kroin, JS, Rinzel, SM, Poore, GA, Todd, GC & Grindey, GB (1990) Evaluation of the antitumor activity of gemcitabine (2′,2′-difluoro-2′-deoxycytidine). Cancer Res 50: 4417–4422.
Le Chevalier, T (1996) Single-agent activity of gemcitabine in advanced non-small cell lung cancer. Semin Oncol 23 (suppl 10) 36–42.
Natale, RB (1998) Experience with new chemotherapeutic agents in non-small cell lung cancer. Chest 113 (suppl 1) 32S–39S.
Non-small Cell Lung Cancer Collaborative Group (1995) Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Br Med J 311: 899–909.
Peters, GJ, Bergman, AM, Ruiz van Haperen, VWT, Veerman, G, Kuiper, CM & Braakhuis, BJM (1995) Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 22 (suppl 11): 72–79.
Savini, S, Zoli, W, Nanni, O, Volpi, A, Frassineti, GL, Magni, E, Flamigni, A, Amadori, A & Amadori, D (1992) In vitro potentiation by lonidamine of the cytotoxic effect of adriamycin on primary and established breast cancer cell lines. Breast Cancer Res Treat 24: 27–34.
Silvestrini, R, Gornati, D, Zaffaroni, N, Bearzatto, A & De Marco, C (1997) Modulation by lonidamine on the combined activity of cisplatin and epidoxorubicin in human breast cancer cells. Breast Cancer Res Treat 42: 103–112.
Skehan, P, Storeng, R, Scudiero, D, Monks, A, McMahon, J, Vistica, D, Warren, J, Bokesch, H, Kenney, S & Boyd, MR (1990) New colorimetric cytotoxic assay for anticancer-drug screening. J Natl Cancer Inst 13: 1107–1112.
Spiridonidis, CH, Laufman, LR, Jones, J, Rhodes, VA, Wallace, K & Nicol, S (1998) Phase I study of docetaxel dose escalation in combination with fixed weekly gemcitabine in patients with advanced malignancies. J Clin Oncol 16: 3866–3873.
Takada, M, Negoro, S, Kudo, S, Furuse, K, Nishikawa, H, Takada, Y, Kamei, T, Niitani, H & Fukuoka, M (1998) Activity of gemcitabine in non-small-cell lung cancer: results of the Japan gemcitabine group (A) phase II study. Cancer Chemother Pharmacol 41: 217–222.
Theodossiou, C, Cook, JA, Fisher, J, Teague, D, Liebmann, JE, Russo, A & Mitchell, JB (1998) Interaction of gemcitabine with paclitaxel and cisplatin in human tumour cell lines. Int J Oncol 12: 825–832.
Van Moorsel, CJA, Veerman, G, Vermoken, JB, Kroep, JR, Van Groeningen, CJ, Voorn, DA, Catik, A, Gall, HE, Eeltink, CM, Van der Vijgh, WJF, Pinedo, HM & Peters, GJ (1998) Schedule dependent changes in the pharmacokinetics (PK) and pharmacodynamics of gemcitabine (GEM) and cisplatin (CP) in patients (pts) with solid tumors. Proc Am Assoc Cancer Res 39: 188
Van Moorsel, CJA, Pinedo, HM, Veerman, G, Guechev, A, Smid, K, Loves, WJ, Vermoken, JB, Postmun, PE & Peters, GJ (1999) Combination chemotherapy studies with gemcitabine and etoposide in non-small cell lung and ovarian cancer cell lines. Biochem Pharmacol, 15;57 (4) 407–415.
Kroep, JR, Voorn, DA, Van Moorsel, CJA, Giaccone, G, Postmus, PE, Rosing, H, Beijnen, JH, Gall, H, Smit, EF, Van Groeningen, CJ, Pinedo, HM & Peters, GJ (1998) Pharmakinetics interaction between paclitaxel (TAX) and gemcitabine (GEM) in patients (pts) with non-small-cell lung cancer (NSCLC). Proc Am Assoc Cancer Res 39: 188
Villa, R, Zaffaroni, N, Orlandi, L, Costa, A, Veronese, S, Vaglini, N & Silvestrini, R (1992) Reliability of a primary system to test cytotoxic drug activity in human malignant melanoma. Int J Oncol 1: 619–624.
Zoli, W, Ricotti, L, Barzanti, L, Dal Susino, M, Frassineti, GL, Milandri, C, Casadei Giunchi, D & Amadori, D (1999) Schedule-dependent interaction of doxorubicin, paclitaxel and gemcitabine in human breast cancer cell lines. Int J Cancer 80: 413–416.
Author information
Authors and Affiliations
Additional information
Correspondence to:W Zoli
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Zoli, W., Ricotti, L., Susino, M. et al. Docetaxel and gemcitabine activity in NSCLC cell lines and in primary cultures from human lung cancer. Br J Cancer 81, 609–615 (1999). https://doi.org/10.1038/sj.bjc.6690737
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690737
Keywords
This article is cited by
-
Inhibition of Survivin Restores the Sensitivity of Breast Cancer Cells to Docetaxel and Vinblastine
Applied Biochemistry and Biotechnology (2014)
-
The efficacy and safety of gemcitabine plus paclitaxel combination first-line therapy for Japanese patients with metastatic breast cancer including triple-negative phenotype
Cancer Chemotherapy and Pharmacology (2011)
-
Randomized phase II study with two gemcitabine- and docetaxel-based combinations as first-line chemotherapy for metastatic non-small cell lung cancer
Journal of Translational Medicine (2008)
-
Phase I/II trial of doxorubicin and fixed dose-rate infusion gemcitabine in advanced soft tissue sarcomas: a GEIS study
British Journal of Cancer (2006)
-
Phase II study of a fixed dose-rate infusion of gemcitabine associated with docetaxel in advanced non-small-cell lung carcinoma
Cancer Chemotherapy and Pharmacology (2005)