Apoptosis induced at different dose rates: implication for the shoulder region of cell survival curves.
Apoptosis is induced by radiation, administered at different dose rates of 3-60 Gy/h, in rat embryo cells transfected with a c-myc oncogene (REC:myc(ch1)) or with a c-Ha-ras oncogene (REC:ras(ch1)). Apoptosis is evaluated in terms of altered morphology, chromatin condensation and DNA fragmentation. The apoptotic dose response of REC:myc(ch1) rises steeply at low doses (to about 40% at 5 Gy), and reaches a plateau at high doses (of about 60% at > 15 Gy). In comparison with REC:myc(ch1), the REC:ras(ch1) is much less susceptible, with a maximum apoptotic fraction of about 10%. Interestingly, radiation-induced apoptosis is nearly dose-rate independent. In parallel, we assessed radiation-induced cell-killing as assayed by colony-formation. In contrast to that observed for apoptosis, the dose response of colony-formation is strongly dependent on dose rate. Cell surviving fraction measured at 3 Gy/h decreases exponentially with dose, with REC:myc(ch1) exhibiting a steeper slope than REC:ras(ch1). Thus, the different low-dose-rate radiosensitivity of the two cell lines may in part be due to their different susceptibility to radiation-induced apoptosis. Taken together, these findings suggest that radiation-induced apoptosis contributes significantly to the initial (shoulder) region of acute dose-rate survival curves of susceptible cells, and may have implications for fractionated and low dose rate radiotherapy.
Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10021.
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D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects*; D002448:Cell Adhesion / Q000235:genetics / Q000528:radiation effects; D016923:Cell Death / Q000235:genetics / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D002843:Chromatin / Q000528:radiation effects / Q000648:ultrastructure; D004247:DNA / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D004622:Embryo, Mammalian; D016259:Genes, myc / Q000528:radiation effects*; D011905:Genes, ras / Q000528:radiation effects*; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000235:genetics; D011878:Radiotherapy; D011879:Radiotherapy Dosage; D051381:Rats; D011916:Rats, Inbred F344; D013234:Stem Cells / Q000528:radiation effects
D002843:Chromatin; D004247:DNA