Abstract 2516: SL01, an oral gemcitabine prodrug as a potent anticancer drug

Abstract

Abstract SL01,dodecyl-3-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)pyrazine-2-carboxylate, is a gemcitabine prodrug synthesized by introducing the moiety of 3-(dodecyloxycarbonyl)pyrazine-2-carbonyl at the N4-position on the cytidine ring of gemcitabine. Our goal is to investigate the efficacy and the safety of this oral prodrug as a potent oral anticancer agent, which may supplant the use of gemcitabine in clinic. The evaluation was accomplished by determining its inhibition of the growth of several tumors with gemcitabine administrated by injection as a control, and also by exploring its pharmacokinetics and its safety. In vivo, SL01 could effectively inhibit the growth of NCI-H460 human non-small cell lung cancer, MCF-7 human breast cancer, BxPC-3 human pancreatic cancer, ES-2 human bladder cancer, HepG2 human hepatocellular carcinoma cells and HCT-116 human colon adenocarcinoma cells in xenografts nude mice without loss their body weight significantly. After three weeks oral administration at the dosage of 30 umol/kg, the inhibition rates were 58.0%, 66.5%, 41.5%, 77.1%, 41.5% and 63.1%, respectively. Molecular analysis indicated that the high efficacy of SL01 was associated with its ability in inducing apoptosis, as evidenced by increase of TUNEL staining cells, activation of caspase-9, caspase-3 and cleaved poly ADP-ribose polymerase in tumor tissues. Pharmacokinetics studies indicated that SL01 exhibited a longer mean retention time and half-life than that of gemcitabine after oral administration in rat, further analysis showed that the bioavailability of SL01 was 22.1%, which indicating that the introduction of 3-(dodecyloxycarbonyl)pyrazine-2-carbonyl moiety to gemcitabine could improve its bioavailability and reduce its first-pass metabolism. The metabolism analysis suggested that SL01 could transform into gemcitabine by hydrolyzing and then releasing into blood to keep the relatively long steady-state concentrations. Toxicity studies indicated that the LD50 was >1.4 g/kg for its acute toxicity, and the tolerated dosage was 45 mg/kg for 4 weeks evaluation in rat. Based on these results, SL01 is proposed as a potent oral anticancer agent, which may supplant the use of gemcitabine in clinic. Acknowledgment: This project was supported by the Ministry of Science and Technology of China (2010ZX09401-302-2-07and 2011ZX09102-001-03). Citation Format: Wenbao Li, Hua Yuan, Xianjun Qu. SL01, an oral gemcitabine prodrug as a potent anticancer drug. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2516. doi:10.1158/1538-7445.AM2014-2516