fig1

Figure 1. 5-FU Resistance can develop through either increased intratumor degradation, decreased anabolic metabolism to FdUMP and/or increased efflux of FdUMP - all of which decrease TS inhibition in tumor cells. 5-FU may be degraded via intratumor DPD, while its anabolic metabolism to FdUMP occurs primarily via UMPS/RRM1/2. Decreased FdUMP levels may result from less efficient conversion through decreased RRM1/2 expression or from increased FdUMP breakdown through elevated expression of NT5E and TP. FdUMP also undergoes efflux from tumor cells by ABC transporters, ABCC10 and ABCC5, that are upregulated upon increased FOXM1 expression in 5-FU-resistant cancer cells. Processes contributing to decreased intra-tumor FdUMP and 5-FU resistance are indicated by red arrows. 5-FU: 5-Fluorouracil; FdUMP: 5-Fluoro-2’-deoxyuridine-5’-O-monophosphate; UMPS: UMP synthase; FBAL: α-fluoro-β-alanine; DPD: dihydropyrimidine Dehydrogenase Deficiency; FUMP: 5-fluorouridine-5'-monophosphate; FUDP: 5-fluorouridine diphospho; FdU: 5-fluoro-2’-deoxyuridine; TK: thymidine kinase; TS: thymidylate synthase; TMP: Trimethylolpropane; RRM: RNA recognition motif; NT5E: ecto-5′-nucleotidase; FOXM1: forkhead box M1; dUMP: 2’-deoxyuridine-5’-O-monophosphate.