P2-128: Sequence dependant antiproliferative effect of cytotoxic drugs and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in non-small cell lung cancer cell lines (NCI-H1975).

Abstract

Introduction: EGFR-TIKs showed about twenty percent of response rate in refractory non-small cell lung cancer. Clinical trials of cytotoxic drugs and EGFR-TIKs failed to show improved survival compared to platinum based doublets. An antagonism between EGFR-TKIs and cytotoxic chemotherapy drugs was raised as a possible explanation for the negative results. Materials and Methods: The antiproliferative effects and cell cycle distributions after treatments with EGFR-TKIs(gefitinib and erlotinib) and cytotoxic drugs(Docetaxel, Paclitaxel, Gemcitabine) were studied using a cell line(NCI-H1975, adenocarcinoma of lung) harboring T790M mutation in exon 20 of EGFR gene. The cell viability assay and cell cycle analysis were performed with MTT assay and flow cytometry. EGFR-TKIs and cytotoxic drugs were treated in different sequences to observe sequence dependent effect. Calcusyn software(Biosoft, Cambridge, UK) was used to calculate combination index(CI). Results: Various combinations of cytotoxic drugs and EGFR-TKIs showed different antiproliferative effects on NCI-H1975 cell line. Antagonisms(CI>1) were observed when EGFR-TKIs were treated before cytotoxic drugs(EC sequence), while synergisms(CI<1) were observed when cytotoxic drugs were pre-treated before EGFR-TKIs(CE sequence). Treatment in EC sequence arrested the cells in G0/G1 phase and decreased the apoptotic fraction. However, treatment in CE sequence arrested the cells in G2/M phase and higher fractions of apoptotic cell death were observed. Conclusion:To combine EGFR-TKIs and cytotoxic drugs, sequence dependent anti-proliferative effects should be considered.