DIFFERENTIAL-EFFECTS OF DOSE-RATE AND SUPERFRACTIONATION ON SURVIVAL AND CELL-CYCLE OF V79 CELLS FROM SPHEROID AND MONOLAYER-CULTURE

Recent developments concerning brachytherapy suggest conditions for an equivalence between the common continuous low dose rate (CLDR) exposu re and pulsed irradiation regimens (PDR), provided that total dose is administered in the same overall time. The respective theoretical cons iderations have been based solely on the phenomenon of sublethal damag e recovery. The present study, therefore, aimed to assess a possible i nfluence of growth state/cell cycle progression when CLDR and differen t super fractionation protocols are compared. The respective experimen ts were performed with V79 cells that can be grown as a rapidly prolif erating monolayer culture or as small spheroids (without hypoxia) wher e most of the cells are out of cycle. Differential changes in cell cyc le distribution occuring during the compared exposure schemes and thei r impact on cell survival were expected to be expressed most clearly w ith this model system because of the short G(1) phase. Cell irradiatio ns were performed with brachytherapy sources either continuously (Cs-1 37) Or With high dose rate pulses (Ir-192) at different (1 h and 4 h) pulse repetitions whereby the overall dose rate was kept constant to a pproximately 1 Gy/h. Cell survival curves were generated by sampling c ells at different exposure times or number of pulses, respectively. Fo r spheroid cells an unequivocal decrease of effectivity was demonstrat ed with decreasing dose per pulse, and the dose effect relation obtain ed with hourly pulses of 1 Gy was indistinguishable from the CLDR resp onse. For monolayer cells, on the contrary, the scheme of hourly pulse s was significantly more effective than the CLDR irradiation. As measu red by flow cytometry, this different behaviour could be attributed to the accumulation of cycling cells in the radiosensitive G(2)/M phase (G(2) block) during protracted exposure which was drastically more pro nounced for the pulsed scheme compared to the CLDR condition. The obse rved principle phenomenon of a block to cell cycle progression from hi gh dose rate pulses (at low overall dose rate) may be less expressed i n (human) cells having a long G(1) period, but if applicable to a clin ical situation, an increase of acute effectiveness of a superfractiona ted brachytherapy protocol has to be considered.