Positive interactive radiosensitisation in vitro with the combination of two nucleoside analogues, (E)-2′-deoxy- 2′-(fluoromethylene) cytidine and iododeoxyuridine

Simultaneous alteration ofde novoandsalvagepathway to the deoxynucleoside triphosphate pool by (E)-2′-Deoxy-(fluoromethylene)cytidine (FMdC) and zidovudine (AZT) results in increased radiosensitivityin vitro

“…We decided to investigate this latter strategy. We did already demonstrate the proof of principle in an earlier paper using the combined effect of FMdC and iodo-deoxy-uridine, but decided to use a compound more readily available for clinical use [23].…”

“…dNTP and NTP levels obtained from HPLC analysis of WiDr cells exposed to FMdC (50 Á100 nM) and AZT at a concentration of 25 ( Figure 3A) and 50 Á100 mM ( Figure 3B). These concentrations were selected based on previous data aimed at optimizing the interpretation of the HPLC technique [1,23,26]. FMdC induces an accumulation of ATP as a result of a cell cycle redistribution effect [1,23].…”

“…These concentrations were selected based on previous data aimed at optimizing the interpretation of the HPLC technique [1,23,26]. FMdC induces an accumulation of ATP as a result of a cell cycle redistribution effect [1,23]. AZT alone does not change the ATP pool.…”

“…The change in the pool, especially the lowering of the dATP, will result in a modification of the activity of the salvag e pathway especially at the level of TK. One might expect a reactive increase of thymidine incorporation, resulting from an increased activity of thymidine kinase (feedback loop on the salvage pathway) [1,21,23,24]. Hence, we decided to investigate whether, the radiosensitizing effect observed after alteration of the de novo pathway by FMdC, could be further modified through manipulation of the salvage pathway, i.e.…”