Figure 4.

TP53-specific liver depletion upregulates the catabolism of 5-FU through DPYD. (A). Liver specific expression of Cre in Albcre;mT/mG;p53^Δ/Δ mice as seen by expression of GFP and normal histology of liver, Bone marrow (BM) and colon in these mice (B) 5-FU treatment schedule for mice (p53^Δ/+ and p53^Δ/Δ) with liver specific deletion of the TP53 gene, [S-1 = First dose Vehicle (6hrs) + second dose 5-FU(30 min)]; S-2 = [First dose 5-FU(6hrs) + second dose 5-FU(30 min)]. (C) Ratio of the amount of 5-FUH₂/5-FU in plasma of liver specific p53 ^{Δ/ +} and p53 ^Δ/Δ genotypes following the treatment plan described in (B) (Values represent median n = 5–7; p = 0.0313 Wilcoxon-rank-sum test). (D) Tumor growth delay (TGD) of syngeneic p53dmc-Ras-Myc colonocytes injected subcutaneously (s.c.) into liver specific p53 ^{Δ/ +} and p53 ^Δ/Δ and treated with vehicle or 5-FU IV (100 mg/kg/week, for a total of 6 weeks) (N = 3–5, Doubling time calculated by exponential growth equation). (E) Analysis of cell death and proliferation in syngeneic tumors on p53 ^{Δ/ +} and p53 ^Δ/Δ at the study in (C) as indicated by number of apoptotic and mitotic nu clei(N = 3). (F) Representative western blot showing expression of DPYD in liver of p53 ^{Δ/ +} and p53 ^Δ/Δ mice with prior treatment of 5-FU for 6 hrs as indicated in (B) and (C).