NCIt definition : An orally available valproic acid prodrug of gemcitabine, a broad-spectrum antimetabolite
and deoxycytidine analogue with antineoplastic activity. Upon administration, gemcitabine
prodrug LY2334737 is hydrolyzed by carboxylesterase 2 (CES2) and releases gemcitabine
systemically over a period of time consistent with formation rate-limited kinetics.
In turn, gemcitabine is converted into the active metabolites difluorodeoxycytidine
diphosphate and triphosphate (dFdCDP and dFdCTP) by deoxycytidine kinase. dFdCDP inhibits
ribonucleotide reductase, thereby decreasing the deoxynucleotide pool available for
DNA replication; dFdCTP is incorporated into DNA, resulting in premature termination
of DNA replication and eventually the induction of apoptosis. Compared to gemcitabine,
this prodrug is able to avoid hydrolysis in enterocytes and the portal circulation
thus avoiding first pass metabolism and increasing systemic gemcitabine availability.
In addition, the slow release of gemcitabine may enhance efficacy while lowering toxicity.
CES2, a serine ester hydrolase, is expressed in certain tumors which may allow for
increased conversion of gemcitabine at the tumor site thus increases cytotoxicity.;