Gemcitabine Prodrug LY2334737
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. [ ]
Term info
Gemcitabine Prodrug LY2334737
- Gemcitabine Prodrug LY2334737
- LY2334737
NCIT_C116978, NCIT_C128784, NCIT_C116977, NCIT_C157711, NCIT_C157712
CTRP
Gemcitabine Prodrug LY2334737
737787
737787
Gemcitabine Prodrug LY2334737
Pharmacologic Substance, Nucleic Acid, Nucleoside, or Nucleotide
C3252354
C102856
Term relations
- Ribonucleotide Reductase Inhibitor
- Pyrimidine Antagonist
- Chemical_Or_Drug_Has_Physiologic_Effect some DNA Synthesis Inhibition
- Chemical_Or_Drug_Has_Mechanism_Of_Action some Enzyme Inhibition
- Chemical_Or_Drug_Has_Physiologic_Effect some Positive Regulation of Apoptosis
- Chemical_Or_Drug_Affects_Gene_Product some Ribonucleotide Reductase
- Chemical_Or_Drug_Has_Physiologic_Effect some Nucleotide Biosynthesis Process