@misc{10481/72604,
year = {2022},
month = {1},
url = {http://hdl.handle.net/10481/72604},
abstract = {5-Fluorouracil (5-FU) is an antineoplastic antimetabolite
that is widely administered to cancer patients by bolus injection,
especially to those suffering from colorectal and pancreatic cancer.
Because of its suboptimal route of administration and dose-limiting
toxicities, diverse 5-FU prodrugs have been developed to confer oral
bioavailability and increase the safety profile of 5-FU chemotherapy
regimens. Our contribution to this goal is presented herein with the
development of a novel palladium-activated prodrug designed to evade
the metabolic machinery responsible for 5-FU anabolic activation and
catabolic processing. The new prodrug is completely innocuous to cells
and highly resistant to metabolization by primary hepatocytes and liver
S9 fractions (the main metabolic route for 5-FU degradation), whereas
it is rapidly converted into 5-FU in the presence of a palladium (Pd) source. In vivo pharmokinetic analysis shows the prodrug is
rapidly and completely absorbed after oral administration and exhibits a longer half-life than 5-FU. In vivo efficacy studies in a
xenograft colon cancer model served to prove, for the first time, that orally administered prodrugs can be locally converted to active
drugs by intratumorally inserted Pd implants.},
organization = {UK Research & Innovation (UKRI)
Engineering & Physical Sciences Research Council (EPSRC)	EP/N021134/1},
organization = {CMVM of the University of Edinburgh},
organization = {European Commission
European Commission Joint Research Centre	H2020MSCA-IF-2014-658833},
organization = {Medical Research Scotland	PHD-1046-2016},
organization = {UK Research & Innovation (UKRI)
Medical Research Council UK (MRC)	MRC/CIC6/52	


UK Research & Innovation (UKRI)},
organization = {Engineering & Physical Sciences Research Council (EPSRC)	PIII024},
publisher = {American Chemical Society},
title = {A 5‑FU Precursor Designed to Evade Anabolic and Catabolic Drug Pathways and Activated by Pd Chemistry In Vitro and In Vivo},
doi = {10.1021/acs.jmedchem.1c01733},
author = {Adam, Catherine and Rubio Ruiz, Belén},
}