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The prodrugs\n                    <jats:bold>\n                      Pt\n                      <jats:sup>IV<\/jats:sup>\n                      P\u20105FUMeOBut\n                    <\/jats:bold>\n                    and\n                    <jats:bold>\n                      Pt\n                      <jats:sup>IV<\/jats:sup>\n                      56\u20105FUMeOBut\n                    <\/jats:bold>\n                    were actualized by derivatising the clinical drug 5\u2010fluorouracil (5FU) and coordinating it to platinum(IV) complexes, leveraging the established cytotoxicity of their platinum(II) precursors,\n                    <jats:bold>\n                      Pt\n                      <jats:sup>II<\/jats:sup>\n                      PHEN\n                      <jats:italic>SS<\/jats:italic>\n                    <\/jats:bold>\n                    and\n                    <jats:bold>\n                      Pt\n                      <jats:sup>II<\/jats:sup>\n                      56ME\n                      <jats:italic>SS<\/jats:italic>\n                    <\/jats:bold>\n                    . The rationale behind this design is to combine the DNA synthesis\u2010disrupting antimetabolite activity of 5FU with platinum\u2010based cytotoxicity, aiming to enhance therapeutic efficacy. This study evaluates the in vitro potency of\n                    <jats:bold>\n                      Pt\n                      <jats:sup>IV<\/jats:sup>\n                      P\u20105FUMeOBut\n                    <\/jats:bold>\n                    and\n                    <jats:bold>\n                      Pt\n                      <jats:sup>IV<\/jats:sup>\n                      56\u20105FUMeOBut\n                    <\/jats:bold>\n                    in colorectal cancer models, assessing their cellular uptake, cytotoxicity, and effects in 3D spheroid cultures. Comparative analyses with cisplatin and 5FU explore their impact on cell survival, reactive oxygen species production, mitochondrial membrane potential, and cell\u2010cycle progression. Mechanistic insights are further examined through apoptosis and necrosis assays, proteomic profiling, and western blot analysis of key signalling pathways. These findings contribute to the preclinical development of fluorouracil\u2010platinum(IV) prodrugs as potential candidates for cancer therapy.\n                  <\/jats:p>","DOI":"10.1002\/chem.202503422","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T03:16:37Z","timestamp":1773026197000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chemotherapeutic Potential of Fluorouracil\u2010Platinum (IV) Prodrugs Against Cisplatin\u2010Resistant Colorectal Cancer Cells"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1478-7006","authenticated-orcid":false,"given":"Maria George","family":"Elias","sequence":"first","affiliation":[{"name":"Faculty of Engineering Computing and Science Western Sydney University  Sydney New South Wales Australia"},{"name":"Faculty of Health School of Medicine Western Sydney University  Sydney New South Wales 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