Short fluorodeoxyuridine exposure of different human glioblastoma lines induces high-level accumulation of S-phase cells that avidly incorporate 125I-iododeoxyuridine

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Abstract

Purpose

Radio-iododeoxyuridine (IdUrd) is a potential Auger radiation therapy agent incorporated into DNA during the synthesis phase. In this study we sought to optimise S-phase targeting by modulating cellular cycling and radio-IdUrd DNA incorporation using short non-toxic fluorodeoxyuridine (FdUrd) incubations.

Methods

Three human glioblastoma cell lines with different p53 expression were pre-treated with various FdUrd conditions. After different intervals, 125I-IdUrd DNA incorporation was measured. Fluorescence-activated cell sorter cell cycle analysis was performed after identical intervals post FdUrd pre-treatment.

Results

The highest increase in 125I-IdUrd DNA incorporation was induced by 1-h incubation with 1 μM FdUrd. Increase in radio-IdUrd DNA incorporation was greatest 16-24 h after FdUrd, reaching factors of ≥7.5 over baseline incorporation in the three cell lines. Furthermore, cell synchronisation in S phase was observed with a peak of ≥69.5% in the three cell lines at 16 and 24 h post FdUrd, corresponding to an increase of 2.5-4.1 over baseline.

Conclusion

FdUrd-induced thymidine synthesis inhibition led to S-phase accumulation that was maximal after an interval of 16-24 h and time-correlated with the highest radio-IdUrd DNA incorporation. These observations might allow the rational design of an Auger radiation therapy targeting a maximal number of S-phase cells in single treatment cycles.

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