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Sensitization of Noncycling Human Diploid Cells to X-Irradiation by Pretreatment with 9-ß-D-Arabinofuranosyladenine¹

Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts 02115

The interactions between X-irradiation and 9-ß-D-arabinofuranosyladenine (ara-A) were studied in confluent, density-inhibited cultures of normal human diploid fibroblast cell strain AG1522. ara-A (0.1 to 3.0 x 10^-3 M) was added to the cultures either 2 or 24 h prior to irradiation. The cells were subcultured at low density to measure the surviving fraction either immediately after irradiation, or they were returned to the incubator in the continued presence of ara-A for an additional 4 or 24 h. In cells subcultured immediately after irradiation, pretreatment with ara-A greatly enhanced cell killing by X-rays in a concentration-dependent fashion. The D₀ of the survival curve decreased from 143 cGy to 74 or 49 cGy following pretreatment with 1.0 or 3.0 x 10^-3 M ara-A, respectively. ara-A by itself had little effect on the cloning efficiency of nonirradiated cells at concentrations up to 10^-3 M, but higher levels were cytotoxic. When subculture was delayed for 4 or 24 h, the enhancement in survival reflecting potentially lethal damage recovery was not reduced by continuing incubation with ara-A at concentrations up to 10^-3 M. Higher levels significantly inhibited potentially lethal damage repair, as well as producing marked sensitization. With 24-h delayed subcultivation, the D₀ of the survival curve decreased from 324 cGy to 63 cGy following incubation with 3.0 x 10^-3 M ara-A. These results indicate that pretreatment with nontoxic concentrations of ara-A can markedly sensitize human cells to the lethal effects of X-rays. This effect appears to be independent of its ability to inhibit postirradiation cellular recovery processes.

¹ Supported by Research Grants CA11751 and CA47542 from the United States National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 7/26/88. Revised 10/21/88. Accepted 11/11/88.