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Wang, Zhe (2014): Schedule-dependent interactions between pemetrexed and vinorelbine in human lung cancer cells. Dissertation, LMU München: Medizinische Fakultät



Lung cancer is the leading cause of cancer deaths worldwide. Despite advances and progresses in surgery, chemotherapy, and radiotherapy over the last decades, the death rate from lung cancer has remained largely unchanged, which is mainly due to metastatic disease and multi drug resistance. Because of the overall poor prognosis, new treatment strategies for lung cancer patients are urgently needed. The aim of this study was to investigate the interactions between pemetrexed and vinorelbine for human adenocarcinoma via various chemotherapy schedules. Vinorelbine and pemetrexed caused a strong dose-dependent cytotoxic effect in both HCC and cisplatin resistant HCC (HCC-res) cells. The IC50 values of vinorelbine against HCC and HCC-res cells were 10.34±1.12 nM and 9.98±2.12 nM, respectively. The IC50 values of Pemetrexed against these cells were 110.77±17.28 nM and 118.89±18.77 nM respectively. The application of different therapy schedules induced a significant time dependent cell growth inhibition on HCC naïve and cisplatin resistant cells. The therapy scheme of cisplatin→pemetrexed→vinorelbine showed the strongest inhibitory effect on both HCC and HCC-res cells. The application of different therapy schedules on HCC and HCC-res cells increased the percentage of cells undergoing apoptosis, except the application of vinorelbine alone. In both HCC and HCC-res cells, cisplatin→pemetrexed→vinorelbine was found the most effective to induce apoptosis. The application of different therapy schedules on HCC and HCC-res cells increased cytoplasma calcium concentration. Only the application of vinorelbine alone failed to increase calcium concentration in HCC cells. The most elevated calcium concentration was found in the cells treated with cisplatin→pemetrexed→vinorelbine in both HCC and HCC-res cells As a conclusion, the sequential application of cisplatin, vinorelbine and pemetrexed has a synergistic effect in cell growth inhibition, apoptosis induction, and calcium concentration elevation in HCC and HCC-res cells. The calcium overload could lead to apoptosis, which was related to the cell growth inhibitory effect of chemotherapeutics in lung cancer cells. It might cast a light to develop chemotherapy schedules for patients, and to overcome cisplatin resistance in lung cancer.