%0 Journal Article
%A Adam, Catherine
%A Bray, Thomas L
%A Pérez-López, Ana M
%A Tan, Ee Hong
%A Rubio-Ruiz, Belén
%A Baillache, Daniel J
%A Houston, Douglas R
%A Salji, Mark J
%A Leung, Hing Y
%A Unciti-Broceta, Asier
%T A 5-FU Precursor Designed to Evade Anabolic and Catabolic Drug Pathways and Activated by Pd Chemistry In Vitro and In Vivo.
%D 2022
%U http://hdl.handle.net/10668/22589
%X 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.
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