REEMERGENCE OF APOPTOTIC CELLS BETWEEN FRACTIONATED DOSES IN IRRADIATED MURINE TUMORS

Purpose: The purpose of this investigation was to follow up our previo us studies on the development of apoptosis in irradiated murine tumors by testing whether an apoptotic subpopulation of cells reemerges betw een fractionated exposures. Methods and Materials: Mice bearing a muri ne ovarian carcinoma, OCa-I, were treated in vivo with two fractionati on protocols: two doses of 12.5 Gy separated by various times out to 5 days and multiple daily fractions of 2.5 Gy. Animals were killed 4 h after the last dose in each protocol, and the percent apoptosis was sc ored from stained histological sections made from the irradiated tumor s according to the specific features characteristic of this mode of ce ll death. Results: The 12.5+12.5 Gy protocol yielded a net total perce nt apoptosis of about 45% when the two doses were separated by 5 days (total dose = 25 Gy), whereas the 2.5 Gy per day protocol yielded abou t 50% net apoptotic cells when given for 5 days (total dose = 12.5 Gy) . These values are to be compared to the value of 36% apoptotic cells that is yielded by large single doses (> 25 Gy). Thus, these results i ndicate that an apoptotic subpopulation of cells reemerged between the fractions in both protocols, but the kinetics appeared to be delayed in the 12.5+12.5 Gy vs. the multiple 2.5 Gy protocol. Conclusion: This reemergence of cells with the propensity for radiation-induced apopto sis between fractionated exposures is consistent with a role for this mode of cell death in the response of tumors to radiotherapy and may r epresent the priming of a new subpopulation of tumor cells for apoptos is as part of normal tumor homeostasis to counterbalance cell division .