SL-01,an oral gemcitabine derivative,was synthesized by introducing the moiety of 3-(dodecyloxycarbonyl) pyrazine-2-carbonyl at the N4-position on the cytidine ring of gemcitabine.Our goal in this study was to evaluate the efficacy of SL-01 on the growth of human cancers with gemcitabine as control.Experiments were performed on human non-small cell lung cancer NCI-H460 and colon cancer HCT-116 both in vitro and in vivo.In vitro assays,SL-01 significantly inhibited the growth of cancer cells as determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay.Further studies indicated that SL-01 induced the cancer cells to apoptosis showing ehromatin condensation and externalization of phosphatidylserine.In vivo studies,we evaluated the efficacy of SL-01 in nude mice bearing human cancer xenografts.SL-01 effectively delayed the growth of NCI-H460 and HCT-116 without significant loss of body weight.Molecular analysis indicated that the high efficacy of SL-01 was associated with its ability in inducing apoptosis as evidenced by increase of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining cells,activation of caspase-9,caspase-3 and cleaved poly ADP-ribose polymerase (PARP) in tumor tissues.SL-01 also increased Bax/Bcl-2 ratio in cancer cells.These biological activities of SL-01 were more potential than that of gemcitabine.Based on these in vitro and in vivo results,SL-01 is proposed as a potent oral anticancer agent that may supplant the use ofgemcitabine in the clinic.