Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human non-small cell lung cancer cells

Tianhong Li, Yi He Ling, I. David Goldman, Roman Perez-Soler

Research output: Contribution to journalArticle

159 Citations (Scopus)

Abstract

Purpose: This study was undertaken to select the optimal combination schedule of erlotinib and pemetrexed for the treatment of relapsed non-small cell lung cancer (NSCLC) using a panel of human NSCLC lines. Experimental Design: Human NSCLC cell lines, with variable expression of the known molecular determinants of erlotinib sensitivity, were exposed to pemetrexed and erlotinib using different schedules. Antitumor effect was measured by growth inhibition by cell count and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell cycle distribution and apoptosis byflow cytometry, and expression of cell cycle mediators by immunoblots. The cytotoxic interaction between pemetrexed and erlotinib (i.e., synergistic, additive, or antagonistic) was determined by median effect analysis. Results: When cells were exposed to concurrent pemetrexed and erlotinib or sequential pemetrexed followed byer lotinib, cytotoxic synergism was observed in both erlotinib-sensitive and erlotinib-resistant human NSCLC cell lines. This was independent of the mutation status of epidermal growth factor receptor or K-Ras genes. Synergism was associated with a combination of cell cycle effects from both agents. In contrast, exposure of cells to erlotinib followed by pemetrexed was mostly antagonistic in erlotinib-sensitive cells and additive at best in erlotinib-resistant cells. Antagonism was associated with erlotinib-induced G1-phase blockade of erlotinib-sensitive cells, which protects cells from pemetrexed cytotoxicity. Pemetrexed induced an epidermal growth factor receptor-mediated activation of the phosphatidylinositol 3-kinase/AKT pathway, which was inhibited byer lotinib and a specific phosphatidylinositol 3-kinase inhibitor, LY294002. Conclusions: The combination of pemetrexed and erlotinib is synergistic in NSCLC in vitro if exposure to erlotinib before pemetrexed is avoided, particularly in tumors that are sensitive to erlotinib. Based on these findings, a randomized phase II study comparing the progression-free survival between an intermittent combination of erlotinib and pemetrexed (experimental arm) and pemetrexed alone (control arm) in patients with relapsing NSCLC has been initiated.

Original languageEnglish (US)
Pages (from-to)3413-3422
Number of pages10
JournalClinical Cancer Research
Volume13
Issue number11
DOIs
StatePublished - Jun 1 2007

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Pemetrexed
Non-Small Cell Lung Carcinoma
Appointments and Schedules
Phosphatidylinositol 3-Kinase
Cell Cycle
Erlotinib Hydrochloride
Epidermal Growth Factor Receptor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human non-small cell lung cancer cells. / Li, Tianhong; Ling, Yi He; Goldman, I. David; Perez-Soler, Roman.

In: Clinical Cancer Research, Vol. 13, No. 11, 01.06.2007, p. 3413-3422.

Research output: Contribution to journalArticle

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abstract = "Purpose: This study was undertaken to select the optimal combination schedule of erlotinib and pemetrexed for the treatment of relapsed non-small cell lung cancer (NSCLC) using a panel of human NSCLC lines. Experimental Design: Human NSCLC cell lines, with variable expression of the known molecular determinants of erlotinib sensitivity, were exposed to pemetrexed and erlotinib using different schedules. Antitumor effect was measured by growth inhibition by cell count and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell cycle distribution and apoptosis byflow cytometry, and expression of cell cycle mediators by immunoblots. The cytotoxic interaction between pemetrexed and erlotinib (i.e., synergistic, additive, or antagonistic) was determined by median effect analysis. Results: When cells were exposed to concurrent pemetrexed and erlotinib or sequential pemetrexed followed byer lotinib, cytotoxic synergism was observed in both erlotinib-sensitive and erlotinib-resistant human NSCLC cell lines. This was independent of the mutation status of epidermal growth factor receptor or K-Ras genes. Synergism was associated with a combination of cell cycle effects from both agents. In contrast, exposure of cells to erlotinib followed by pemetrexed was mostly antagonistic in erlotinib-sensitive cells and additive at best in erlotinib-resistant cells. Antagonism was associated with erlotinib-induced G1-phase blockade of erlotinib-sensitive cells, which protects cells from pemetrexed cytotoxicity. Pemetrexed induced an epidermal growth factor receptor-mediated activation of the phosphatidylinositol 3-kinase/AKT pathway, which was inhibited byer lotinib and a specific phosphatidylinositol 3-kinase inhibitor, LY294002. Conclusions: The combination of pemetrexed and erlotinib is synergistic in NSCLC in vitro if exposure to erlotinib before pemetrexed is avoided, particularly in tumors that are sensitive to erlotinib. Based on these findings, a randomized phase II study comparing the progression-free survival between an intermittent combination of erlotinib and pemetrexed (experimental arm) and pemetrexed alone (control arm) in patients with relapsing NSCLC has been initiated.",
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AU - Goldman, I. David

AU - Perez-Soler, Roman

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N2 - Purpose: This study was undertaken to select the optimal combination schedule of erlotinib and pemetrexed for the treatment of relapsed non-small cell lung cancer (NSCLC) using a panel of human NSCLC lines. Experimental Design: Human NSCLC cell lines, with variable expression of the known molecular determinants of erlotinib sensitivity, were exposed to pemetrexed and erlotinib using different schedules. Antitumor effect was measured by growth inhibition by cell count and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell cycle distribution and apoptosis byflow cytometry, and expression of cell cycle mediators by immunoblots. The cytotoxic interaction between pemetrexed and erlotinib (i.e., synergistic, additive, or antagonistic) was determined by median effect analysis. Results: When cells were exposed to concurrent pemetrexed and erlotinib or sequential pemetrexed followed byer lotinib, cytotoxic synergism was observed in both erlotinib-sensitive and erlotinib-resistant human NSCLC cell lines. This was independent of the mutation status of epidermal growth factor receptor or K-Ras genes. Synergism was associated with a combination of cell cycle effects from both agents. In contrast, exposure of cells to erlotinib followed by pemetrexed was mostly antagonistic in erlotinib-sensitive cells and additive at best in erlotinib-resistant cells. Antagonism was associated with erlotinib-induced G1-phase blockade of erlotinib-sensitive cells, which protects cells from pemetrexed cytotoxicity. Pemetrexed induced an epidermal growth factor receptor-mediated activation of the phosphatidylinositol 3-kinase/AKT pathway, which was inhibited byer lotinib and a specific phosphatidylinositol 3-kinase inhibitor, LY294002. Conclusions: The combination of pemetrexed and erlotinib is synergistic in NSCLC in vitro if exposure to erlotinib before pemetrexed is avoided, particularly in tumors that are sensitive to erlotinib. Based on these findings, a randomized phase II study comparing the progression-free survival between an intermittent combination of erlotinib and pemetrexed (experimental arm) and pemetrexed alone (control arm) in patients with relapsing NSCLC has been initiated.

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