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Potentiation of Cell Killing by Low-Dose-Rate Radiation by Camptothecin Is Related to an Increase in the Level of DNA Double-Strand Breaks

Daron G. Owen, James P. McNamee, G. Peter Raaphorst and Cheng E. Ng
Radiation Research
Vol. 157, No. 2 (Feb., 2002), pp. 149-157
Stable URL: http://www.jstor.org/stable/3580956
Page Count: 9
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Potentiation of Cell Killing by Low-Dose-Rate Radiation by Camptothecin Is Related to an Increase in the Level of DNA Double-Strand Breaks
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Abstract

We investigated the ability of camptothecin to potentiate cell killing by low-dose-rate irradiation and whether this potentiation was associated with an increase in the level of residual DNA double-strand breaks (DSBs). Human melanoma (Sk-Mel-3) cells, grown to the confluent phase, were treated with low-dose-rate radiation (0.88 cGy/min) alone, camptothecin alone, or concurrent camptothecin and low-dose-rate radiation. Cell survival was determined using a clonogenic assay. The interactions between camptothecin and low-dose-rate radiation were analyzed further using isobolograms. DNA DSBs were determined using the neutral comet assay. We found that 10 and 25 μM camptothecin, but not 1 μM, camptothecin potentiated cell killing significantly relative to that seen with low-dose-rate radiation alone. Unexpectedly, the potentiation of the effects of low-dose-rate radiation by camptothecin was accompanied by large increases in the α parameter of the linear-quadratic fit rather than in the β parameter. This suggests a modification of intrinsic radiosensitivity rather than of repair of sublethal damage. From isobologram analysis, low-dose-rate radiation interacted either additively or supra-additively with 25 or 10 μM camptothecin. Conversely, the interaction of low-dose-rate radiation with 1 μM camptothecin was subadditive. Finally, there were strong correlations (correlation coefficients >0.9) between surviving fraction and either comet tail length or comet tail moment after concurrent treatment with 25 μM camptothecin and low-dose-rate radiation. This suggests that the level of residual DNA DSBs was a good indicator of cell killing after treatment with low-dose-rate radiation plus 25 μM camptothecin.

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