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Effects of Inhibitors of DNA Strand Break Repair on HeLa Cell Radiosensitivity¹

Division of Radiation Biology, Department of Radiology, School of Medicine, University of California, San Diego, La Jolla, California 92093

The effects of three drugs (hydroxyurea, 1-ß-D-arabinofuranosylcytosine, and diamide) known to inhibit DNA synthesis on the repair of ionizing radiation-induced DNA single-strand breaks measured by alkaline elution and on cellular radiosensitivity were examined. Inhibition of repair was observed at 10^-2 M hydroxyurea, 10^-4 M 1-ß-D-arabinofuranosylcytosine, and 5 x 10^-5 M diamide, levels causing only 10% cell kill. While the mechanisms by which the drugs inhibit DNA synthesis differ, they are equally effective at inhibiting repair; without drug, cells, after a dose of 10 grays, repair 35% of DNA strand breaks in 3 min and a further 35% in 1 hr; with drug, only 10% is repaired in 3 min, and the deficiency in repair amount remains, even after 60 min. The effect of similar drug treatment on radiation-induced cell killing shows that radiosensitivity is increased; the major effect is reduction in D₀ from 1.3 grays to 0.8 grays with smaller effects on D_q. The data are consistent with the hypothesis that radiation produces potential double-strand breaks in DNA which, if not rapidly repaired, are converted into lethal actual double-strand breaks.

¹ This investigation was supported by USPHS Grant CA26279 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Division of Radiation Biology, Department of Radiology, M-010, University of California, San Diego, La Jolla, Calif. 92093.

³ Supported by USPHS Grant CA09290 awarded by the National Cancer Institute. Present address: Department of Experimental Hematology, AFRRI, Building 42, Bethesda, Md. 20814.

Received 4/ 5/83. Accepted 9/26/83.