Role of apoptosis in low-dose hyper-radiosensitivity.
Little is known about the mode of cell killing associated with low-dose hyper-radiosensitivity, the radiation response that describes the enhanced sensitivity of cells to small doses of ionizing radiation. Using a technique that measures the activation of caspase 3, we have established a relationship between apoptosis detected 24 h after low-dose radiation exposure and low-dose hyper-radiosensitivity in four mammalian cell lines (T98G, U373, MR4 and 3.7 cells) and two normal human lymphoblastoid cell lines. The existence of low-dose hyper-radiosensitivity in clonogenic survival experiments was found to be associated with an elevated level of apoptosis after low-dose exposures, corroborating earlier observations (Enns et al., Mol. Cancer Res. 2, 557-566, 2004). We also show that enriching populations of MR4 and V79 cells with G(1)-phase cells, to minimize the numbers of G(2)-phase cells, abolished the enhanced low-dose apoptosis. These cell-cycle enrichment experiments strengthen the reported association between low-dose hyper-sensitivity and the radioresponse of G(2)-phase cells. These data are consistent with our current hypothesis to explain low-dose hyper-radiosensitivity, namely that the enhanced sensitivity of cells to low doses of ionizing radiation reflects the failure of ATM-dependent repair processes to fully arrest the progression of damaged G(2)-phase cells harboring unrepaired DNA breaks entering mitosis.
Krueger
S A
SA
Department of Radiation Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA.
Joiner
M C
MC
Weinfeld
M
M
Piasentin
E
E
Marples
B
B
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation / Q000528:radiation effects; D006801:Humans; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000528:radiation effects*
D053148:Caspase 3