Effects of gemcitabine on APE/Ref-1 and the therapeutic potential of antisense oligonucleotides

Apurinic/apyrimidinic endonuclease (APE) is a key enzyme involved in DNA base excision repair and is also referred to as redox effective factor (Ref-1) due to its alternative role as a redox regulator of various transcription factors like NF-kappaB and p53. Pancreatic cancer is extremely resistant to various types of cancer treatment with the only currently clinically active agent being the nucleoside analogue; gemcitabine. Pancreatic cells treated with various doses of gemcitabine showed increases in APE/Ref-1 protein levels as well as increased endonuclease activity. These results suggest that elevated APE/Ref-1 expression might be an adaptive response contributing to the overall chemoresistance seen in pancreatic carcinomas. Combination treatments with antisense and gemcitabine inhibited further induction of APE/Ref-1 protein versus cells exposed to gemcitabine alone. This study suggests that APE/Ref-1 is an important mediator of gemcitabine resistance and that antisense have a potentially therapeutic role in the treatment of pancreatic cancers.