Gemcitabine is a nucleoside analog used as chemotherapy. It is marketed as Gemzar® by Eli Lilly and Company. Gemcitabine inhibits thymidylate synthetase, leading to inhibition of DNA synthesis and cell death. Gemcitabine is a prodrug so activity occurs as a result of intracellular conversion to two active metabolites, gemcitabine diphosphate and gemcitabine triphosphate by deoxycitidine kinase. Gemcitabine diphosphate also inhibits ribonucleotide reductase, the enzyme responsible for catalyzing synthesis of deoxynucleoside triphosphates required for DNA synthesis. Finally, Gemcitabine triphosphate (diflurorodeoxycytidine triphosphate) competes with endogenous deoxynucleoside triphosphates for incorporation into DNA. Gemcitabine is indicated for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy; metastatic ovarian cancer; inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer; and locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas.

LY2334737 an orally active amide prodrug of gemcitabine, a nucleoside analog chemotherapeutic with a broad spectrum of anti-tumor activity against several human malignancies including pancreatic, ovarian, lung, breast, and bladder. LY2334737 was developed to be absorbed intact and cleaved in vivo, releasing gemcitabine and valproic acid to achieve prolonged systemic exposure, good efficacy with lower toxicity along with added flexibility of administration and greater patient convenience. The hydrolysis and pharmacokinetics of LY2334737 and its downstream metabolites was evaluated in preclinical in vitro and in vivo experiments in mice, rats, and dogs, which demonstrated the prodrug is absorbed largely intact across the intestinal epithelium and delivers LY2334737 to systemic circulation. The hydrolysis of LY2334737 is relatively slow, resulting in sustained release of gemcitabine in vivo. A major enzyme involved in the hydrolysis of LY2334737 is carboxylesterase 2 (CES2). The compound has entered clinical trials and is being evaluated as a potential new anticancer agent.