A 5‑FU Precursor Designed to Evade Anabolic and Catabolic Drug Pathways and Activated by Pd Chemistry In Vitro and In Vivo
Metadatos
Mostrar el registro completo del ítemEditorial
American Chemical Society
Fecha
2022-01-03Referencia bibliográfica
J. Med. Chem. 2022, 65, 1, 552–561. [https://doi.org/10.1021/acs.jmedchem.1c01733]
Patrocinador
UK Research & Innovation (UKRI) Engineering & Physical Sciences Research Council (EPSRC) EP/N021134/1; CMVM of the University of Edinburgh; European Commission European Commission Joint Research Centre H2020MSCA-IF-2014-658833; Medical Research Scotland PHD-1046-2016; UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MRC/CIC6/52 UK Research & Innovation (UKRI); Engineering & Physical Sciences Research Council (EPSRC) PIII024Resumen
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.