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Published on: July 3, 2015
Early and Late Effects of Difluorodeoxycytidine on Murine Cell Radiosensitivity In Vivo
Virginia Cruz-Vallejo1, Teresita Vallarino-Kelly1, Sofía López-Pavón1
1Biology Department, Instituto Nacional de Investigaciones Nucleares, México City, México.
Background/Aim:
Difluorodeoxycytidine (dFdC) has been reported to increase radiosensitivity, although its mechanism of action is unknown. The objective of this study was to determine the early and late effects of dFdC on mouse cell radiosensitivity in vivo.
Materials And Methods:
The early effects of dFdC on bone marrow cell radiosensitivity were evaluated a few minutes after dFdC treatment using single-cell gel electrophoresis. Four groups of mice were set up: non-treated, dFdC-treated, radiation-treated, and dFdC plus radiation-treated. To evaluate the late effects of dFdC, the kinetics of micronucleus production and the inhibition of proliferation were measured in mouse normoblasts in vivo.
Results:
The early radiosensitization index was 1.7 and correlated with the proportion of severely damaged cells, likely in S phase. Late effects of dFdC were additive with radiation in both micronucleus induction and cytotoxicity. The pattern and duration of micronucleus formation suggest a dependency on dFdC incorporation into DNA. Although cytotoxicity increased over time, it did not influence the radiosensitization index.
Conclusion:
dFdC enhances early radiosensitivity in bone marrow cells, likely by inhibiting DNA synthesis and generating reactive oxygen species (ROS)-induced DNA breaks. Late genotoxic effects were additive and kinetically linked to dFdC incorporation. Both dFdC alone and in combination with radiation exerted prolonged cytotoxic effects on normoblast precursors, with slightly greater toxicity observed in the combination group.
