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. 2021 Apr 6;7:38. doi: 10.1038/s41523-021-00245-5

Fig. 9. Schematic illustration of mechanisms influencing the combination of dUTPase inhibition with fluoropyrimidine and/or anthracyclines.

Fig. 9

a Schematic demonstrating the hypothesised consequences of combined dUTPase inhibition by CV6-530 and TS inhibition by fluoropyrimidine (e.g., 5-Fluorouracil (5-FU) or FUdR). Inhibition of dUTPase subsequently caused dUTP and FdUTP pool accumulation, while concurrent TS inhibition by FdUMP leads to TTP pool depletion. In combination, this leads to an increased (F)dUTP:TTP ratio and subsequent uracil misincorporation into DNA. Due to the persistent increase in dUTP:TTP pools there is a futile cycle of base excision repair (BER) leading to increased DNA damage and subsequently increased cell death. b Anthracyclines induce DNA double-strand breaks (DSBs) through inhibition of Topoisomerase 2 (Top2). The DNA DSBs are then repaired by non-homologous end-joining (NHEJ) or homologous repair (HR) leading to either cell survival or cell death depending on the success of the repair. c Anthracyclines induce DNA DSBs through inhibition of Top2. However, inhibition of dUTPase leads to dUTP pool accumulation following the phosphorylation of dUMP/dUDP. The resulting accumulation of dUTP pools leads to uracil misincorporation during the new DNA synthesis phase of DSB repair. Subsequent uracil-DNA repair by base excision repair (BER) compromised DSB repair leading to extensive DNA damage and increased cell death.