SAHA (Histone deacetylase inhibitor) enhanced 5-FU sensitivity by downregulation of TS (Thymidylate Synthase) expression in lung cancer cells.

728 Several HDAC inhibitors including SAHA, are show promosing antitumor activity. Here ,we report these synergistic effect with 5-FU therapy in lung cancer cells. Using the MTT assay , we analyzed the growth-inhibitory effect of 5-FU and SAHA against 8 lung cancer cell lines. The mRNA and protein of TS,DPD,OPRT and TP, which have been reported related to 5-FU sensitivity and resistance , were analyzed in these lines. One 5-FU-sensitive line had no DPD expression, and seven 5-FU resistant lines had TS and DPD overexpression. Combined treatment with low dose SAHA enhanced 5-FU mediated cytoxicity in 5-FU-resistant cells. SAHA downreguleted TS mRNA , protein and increased their expression followed by 5-FU treatment . In orde to clarify the mechanism of downregulation of TS mRNA expression, we are examining the promoter states of TS gene related histone acetylation and E2F-1 transcript activity.
 We conclude that a combination therapy using HDAC inhibitor and 5FU may be useful at overcoming 5-FU resistance in lung cancer.