1-beta-D-arabinofuranosylcytosine is cytotoxic in quiescent normal lymphocytes undergoing DNA excision repair.

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We have sought to clarify the potential activity of the S‐phase‐specific antileukemic agent 1‐β‐D‐arabinofuranosylcytosine (ara‐C), an inhibitor of DNA synthesis, in quiescent cells that are substantially non‐sensitive to nucleoside analogues. It was hypothesized that the combination of ara‐C with DNA damaging agents that initiate DNA repair will expand ara‐C cytotoxicity to non‐cycling cells. The repair kinetics, which included incision of damaged DNA, gap‐filling by DNA synthesis and rejoining by ligation, were evaluated using the single cell gel electrophoresis (Comet) assay and the thymidine incorporation assay. When normal lymphocytes were treated with ultraviolet C or with l,3‐bis(2‐chloroethyl)‐1‐nitrosourea (BCNU), the processes of DNA excision repair were promptly initiated and rapidly completed. When the cells were incubated with ara‐C prior to irradiation or BCNU treatment, the steps of DNA synthesis and rejoining in the repair processes were both inhibited. The ara‐C‐mediated inhibition of the repair processes was concentration‐dependent, with the effect peaking at 10 μM. The combination of ara‐C with these DNA repair initiators exerted subsequent cytotoxicity, which was proportional to the extent of the repair inhibition in the presence of ara‐C. In conclusion, ara‐C was cytotoxic in quiescent cells undergoing DNA repair. This might be attributed to unrepaired DNA damage that remained in the cells, thereby inducing lethal cytotoxicity. Alternatively, ara‐C might exert its own cytotoxicity by inhibiting DNA synthesis in the repair processes. Such a strategy may be effective against a dormant subpopulation in acute leukemia that survives chemotherapy.