NCIt definition : A pyrimidine analogue and a proprietary prodrug based on an aryloxy phosphoramidate
derivative of gemcitabine with potential antineoplastic activity. Upon intravenous
administration and cellular uptake, fosgemcitabine palabenamide is converted into
the active metabolites difluorodeoxycytidine di- and triphosphate (dFdCDP, dFdCTP).
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 induction of apoptosis. With the phosphoramidate
moiety on the gemcitabine monophosphate group, NUC-1031 has improved properties over
its parent molecule: 1) is more lipophilic and accumulates in cancer cells by passive
diffusion and does not require a nucleoside transporter, 2) as the agent is delivered
in the monophosphate form, the first phosphorylation step by deoxycytidine kinase
is not required, 3) this agent is not susceptible to deactivation by cytidine deaminase
cleavage of the monophosphorylated form. Altogether, this may help overcome resistance
to gemcitabine.;