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Strand Breaks in DNA from Normal and Transformed Human Cells Treated with 1,3-Bis(2-chloroethyl)-1-nitrosourea

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20014

The DNA of human cells treated with 1,3-bis(2-chloroethyl)-1-nitrosourea was examined for the appearance of single-strand breaks or alkali-labile sites. Normal human embryo fibroblasts (WI-38) were compared with an SV40-transformed derivative line (VA-13) which was found to have an increased sensitivity to the cytotoxic actions of the drug. Drug treatment induced single-strand breaks and/or alkali-labile sites in both cell types as measured by two methods: alkaline sedimentation (conducted at pH 13) and alkaline elution (conducted at pH 12.1). The apparent single-strand break frequencies (which may include alkalilabile sites) were much greater when measured by alkaline sedimentation than when measured by alkaline elution. When measured by alkaline sedimentation, the apparent break frequencies were greater in WI-38 cells than in VA-13 cells, whereas by alkaline elution the reverse was true. The results may reflect differences between the two cell types in the relative frequencies of drug-induced alkalilabile sites as opposed to actual single-strand breaks.

The DNA breaks and/or alkali-labile sites appear to be repaired upon replacement of drug treatment medium with fresh medium. If the medium was not replaced, there was no repair, even after times much longer than the reported half-times for 1,3-bis(2-chloroethyl)-1-nitrosourea decomposition. This might be due to an inhibitory effect of a relatively stable drug product or to a stimulatory effect of fresh medium. The apparent rates of repair were similar in the two cell types studied.

¹ To whom requests for reprints should be addressed.

Received 5/25/76. Accepted 7/15/77.

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