Potentiation of cytotoxicity and radiosensitization of (E)-2'-deoxy-2' (fluoromethylene) cytidine by pentoxifylline in vitro.

(E)-28-deoxy-28-(fluoromethylene) cytidine (FMdC), a novel
inhibitor of ribonucleotide-diphosphate reductase, has been
shown to have anti-tumor activity against solid tumors and
sensitize tumor cells to ionizing radiation. Pentoxifylline
(PTX) can potentiate the cell killing induced by DNAdamaging
agents through abrogation of DNA-damagedependent
G2 checkpoint. We investigated the cytotoxic,
radiosensitizing and cell-cycle effects of FMdC and PTX in a
human colon-cancer cell line WiDr. PTX at 0.25–1.0 mM
enhanced the cytotoxicity of FMdC and lowered the IC50 of
FMdC from 79 6 0.1 to 31.2 6 2.1 nM, as determined by MTT
assay. Using clonogenic assay, pre-irradiation exposure of
exponentially growing WiDr cells to 30 nM FMdC for 48 hr or
post-irradiation to 0.5 to 1.0 mM PTX alone resulted in an
increase in radiation-induced cytotoxicity. Moreover, there
was a significant change of the radiosensitization if both drugs
were combined as compared with the effect of either drug
alone. Cell-cycle analysis showed that treatment with nanomolar
FMdC resulted in S-phase accumulation and that such
an S-phase arrest can be abrogated by PTX. Treatment with
FMdC prior to radiation increased post-irradiation-induced
G2 arrest, and such G2 accumulation was also abrogated by
PTX. These results suggest that pharmacological abrogation
of S and G2 checkpoints by PTX may provide an effective
strategy for enhancing the cytotoxic and radiosensitizing
effects of FMdC. Int. J. Cancer 80:155–160, 1999.