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Explaining Differences in Sensitivity to Killing by Ionizing Radiation between Human Lymphoid Cell Lines

Sir Donald and Lady Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne, Victoria 3002, Australia

We surveyed five human hematopoietic cell lines (HSB-2, MOLT-4, Reh, CEM, and HL-60) to determine whether any simple correlates with sensitivity to killing by -irradiation might be revealed. The clonogenic survival -ray dose-response curves for these cell lines cover a wide range of sensitivities. Consistent with previous results for murine hematopoietic cell lines, there was a clear correlation between the rapidity with which irradiation induced apoptosis and clonogenic radiosensitivity of a cell line, although the relationship between timing of apoptosis and radiosensitivity differed between human and murine cell lines. Flow cytometric determination of cell cycle distribution after irradiation showed that differences between human hematopoietic cell lines, in the rate of induction of apoptosis, were generally related to the functioning of cell cycle checkpoints. Whereas the rapidly dying and radiosensitive HSB-2 cell line underwent apoptosis from different points in the cell cycle, the more slowly dying cell lines showed a variety of cell cycle arrest profiles and initiated apoptosis after accumulation of cells in the G₂ phase. The lag-phase between arrest in G₂ and induction of apoptosis was comparable for MOLT-4, Reh, and CEM; however, HL-60 cells showed a markedly longer G₂ arrest that correlated with their greater radioresistance. The results suggest that the total length of time available for DNA damage repair (irrespective of whether this time accrues as blockage in G₁, S, or G₂), prior to potential activation of apoptosis, is a critical determinant of radiosensitivity in human hematopoietic cell lines. Comparison of the p53 status of these cell lines suggested that mutations in the TP53 gene are contributing to the delay of induction of apoptosis seen in the more radioresistant cell lines. The sensitivity of MOLT-4 and HL-60 cells to killing by DNA-associated ¹²⁵I decays was determined and was found to correlate with the relative sensitivity of these lines to -irradiation. The highly localized deposition of energy by ¹²⁵I decays argues that DNA damage is a potent initiator of apoptosis in these cell lines. The results presented suggest that differences in the radiosensitivity of the cell lines examined reflect differences in the rapidity of induction of apoptosis and that radiation-induced cell death in hematopoietic cells can be explained as a response to DNA damage.

¹ To whom requests for reprints should be addressed, at Research Division, Peter MacCallum Cancer Institute, Locked Bag No. 1, A'Beckett Street, Melbourne, Victoria 8006, Australia. Phone: 61-3-9656-1291; Fax: 61-3-9656-1411; E-mail: i.radford@pmci.unimelb.edu.au.

Received 12/ 9/97. Accepted 4/23/98.

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