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Radiation-induced Apoptosis: Effects of Cell Age and Dose Fractionation¹

Laboratory of Radiation Biophysics and Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York 10021

The cell cycle dependence of radiation-induced apoptosis was measured using mitotically synchronized REC:myc(ch1) and Rat1:myc_b cells. Cells in S and G₂ phases were more susceptible; the apoptotic fraction was about 0.7–0.8 as compared to about 0.4 for G₁ cells at a dose of 10 Gy. Two-dimensional cytofluorimetric analysis of cells, pulsed-labeled with bromodeoxyuridine and then irradiated with 10 Gy, showed both G₁ and G₂ blocks (6–8 h) for REC:myc(ch1) cells but only G₂ block for Rat1:myc_b cells. Consistent with these results, wild-type p53 and WAF1 (or p21), known to play a role in G₁ delay, was induced by radiation in REC:myc(ch1) but not in Rat1:myc_b cells. The cell cycle dependence of radiation-induced apoptosis and the absence of a G₁ block for Rat1:myc_b cells led to the prediction and observation of the novel "inverse split-dose effect," i.e., a radiation dose given in two equal halves separated by a few hours yielded a higher level of apoptosis relative to that resulting from the same total dose given all at once. This effect is due to cell cycle progression from G₁ to the more sensitive S-G₂ phase during the interval between the split doses. In contrast, the inverse split-dose effect for apoptosis is absent for REC:myc(ch1), due presumably to the radiation-induced G₁ delay. Parallel split-dose experiments, but using clonogenic survival as end points, show recovery for REC:myc(ch1) cells but not for Rat1:myc_b cells, reflecting the influence of split-dose, radiation-induced apoptosis.

¹ Supported in part by National Cancer Institute Grant CA52713 (NIH, United States Department of Health and Human Services).

² To whom requests for reprints should be addressed, at Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

Received 7/27/95. Accepted 10/ 5/95.

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