Chemo-radiotherapy: Radiosensitizing nucleoside analogues (Review)

The available knowledge on potential radiosensitizing nucleoside analogues with special focus on fludarabine and gemcitabine is reviewed. These analog ues are prodrugs whose active triphosphate forms inhibit various enzymes in volved in DNA synthesis and repair. Several properties of these analogues s upport their use as radiosensitizers. As repair inhibitors, they have the p otential to increase the amount of residual DNA and chromosome damage after irradiation, and as DNA synthesis inhibitors, they specifically target the S-phase cell component and could thus overcome the detrimental effect of t umor clonogen repopulation during fractionated irradiation. Also, through t heir cytotoxic effect, these analogues could increase tumor cell loss, faci litating tumor reoxygenation, and thus obviate tumor hypoxia's inhibitory e ffect on radio-response. Induction of DNA damage in all phases of the cell cycle by irradiation could create DNA sites for drug incorporation, possibl y inducing an apoptotic response in cells outside of S-phase. Experimental data addressing these hypotheses are reviewed and updates on ongoing clinic al trials combining fludarabine or gemcitabine and irradiation are given.