The repair of DNA damage caused by
chemotherapy in
cancer cells occurs mainly at two cell cycle checkpoints (G1 and G2) and is
a factor contributing to chemoresistance. Most
colorectal cancers harbor mutations in p53, the main pathway involved in the G1 checkpoint, and thus, are particularly dependent on the G2 checkpoint for DNA repair. The present study examined the effect of
AZD6738, a specific inhibitor of
ataxia telangiectasia mutated and rad3‑related (ATR) involved in the G2 checkpoint, combined with 5‑fluorouracil (5‑FU), a central chemotherapeutic agent, on
colorectal cancer cells. Since 5‑FU has a DNA‑damaging effect, its combination with
AZD6738 is likely to enhance the
therapeutic effect. The effects of the
AZD6738/5‑FU combination were evaluated in various
colorectal cancer cells (HT29, SW480, HCT116 and DLD‑1 cells) by flow cytometry (HT29 cells), western blotting (HT29 cells) and water‑soluble tetrazolium 1 assays (HT29, SW480, HCT116 and DLD‑1 cells), as well as in an experimental animal model (HT29 cells). In vitro, the
AZD6738/5‑FU combination increased the number of mitotic cells according to flow cytometry, decreased the checkpoint kinase 1 phosphorylation levels and increased cleaved caspase‑3 and phosphorylated form of H2A.X variant
histone levels according to western blotting, and decreased the proliferation rate of four
colon cancer cell lines according to cell viability experiments. In vivo, xenografted
colorectal cancer cells treated with the
AZD6738/5‑FU combination exhibited a marked decrease in proliferation compared with the 5‑FU alone group. The present results suggested that
AZD6738 enhanced the effect of 5‑FU in p53‑mutated
colorectal cancer.