Investigation of Pemetrexed(Alimta)cytotoxicity with non-small cell lung cancer cell lines

• Main Authors: Chia-Chia, 劉佳佳
• Other Authors: 許國堂
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/78889810485026980166

碩士 === 中山醫學大學 === 醫學分子毒理學研究所 === 95 === Lung cancer is the leading cause of cancer deaths worldwide . Non-small cell lung cancer (NSCLC) accounts for about 85 %, while SCLC accounts for the rest 15 %, especially the prognosis for any patient with surgery progressive remains poor. In spite of new treatments, the overall five-year survival rate remains about 14 % and most patients present with advanced disease. Pemetrexed is a newly developed multitarget antifolate and it inhibits thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT), and dihydrofolate reductase (DHFR). Additionally, preclinical animal studies have suggested that folic acid and vitamin B12 supplementation reduce the risk for severe drug-induced toxicities while preserving the antitumor activity of Pemetrexed. The aim of the present study was to evaluate the cytotoxicity of Pemetrexed and to investigate the effects of folic acid and vitamin B12 supplement in Pemetrexed sensitivity with NSCLC cell lines (A549, H1299, A549-p53 RANi, H1299/p53). Pemetrexed was more cytotoxic to the cells when treated in medium containing 2 % serum than those with 5 % and 10 % serum. We found that folic acid/vitamin B12 supplementation resulted in sensitization of cells to Pemetrexed treatment under 10 % serum conditions. We also showed high concentration of vitamin B12 affects sensitivity to Cisplatin but not Gencitabine. However, when pemetrexed-resistant cell lines from H1299 cells were treated with Pemetrexed/vitamin B12 the sensitization effect was not observed. The Rb protein was decreased in Pemetrexed treated A549 cells but not in H1299 cells by western immunoblotting. Furthermore, we found CL1-0 and CL1-5 of Taiwanese lung cancer cell lines were more sensitive to Pemetrexed than A549 cell line by MTS assay.