Influence of circadian rhythms on radiosensitivity: single and fractionated dose studies in mouse skin

In rodent skin significant increases in labelling and mitotic indices have been reported during the period of maximum nocturnal activity. It has been suggested that sparing of radiation damage in fast-proliferating normal tissues could be achieved if treatments were given at the time of day when the maximum number of normal cells were most radioresistant. If changes in radiosensitivity do occur in tissues with circadian fluctuations in the cell kinetic parameters, then the magnitude of these changes should be dependent on the size of dose per fraction. Because of the implications for clinical radiotherapy, especially in regimes where multiple fractions per day are given (MFD), possible diurnal variations in radiosensitivity were investigated using single dose and fractionated X-ray regimens (5F/5 days, 8F/8 days), in rodent skin. Treatments were delivered at 1, 3, 5 a.m. (time of highest DNA synthetic activity in mouse epidermis), 6 and 7 a.m. (highest mitotic activity) and at 5 p.m. (minimum labelling and mitotic indices). To investigate a large range of doses per fraction, fractionated X-rays were given alone or followed by neutron top-up doses. Using a range of doses per fraction of 30 Gy down to 1 Gy, we did not detect any change in radiosensitivity with any of the schedules. Our results suggest that a decrease in normal tissue tolerance is unlikely to be observed in patients even if irradiated at a time of day at which a maximum increase in radiosensitivity might be predicted on the basis of a high mitotic index.