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Imbalance of Deoxyribonucleoside Triphosphates, DNA Double-Strand Breaks, and Cell Death Caused by 2-Chlorodeoxyadenosine in Mouse FM3A Cells¹

Faculty of Pharmaceutical Sciences [Y. H., A. Y., S. T., K. W., Y. W.], Okayama University, Tsushima, Okayama 700; Fujisaki Cell Center [T. O., J. M.], Hayashibara Biochemical Laboratories, Inc., 675-1 Fujisaki, Okayama 702; and Faculty of Pharmaceutical Sciences [A. M., T. U.], Hokkaido University, Sapporo, Hokkaido 060, Japan

The mechanism of the cytotoxic action of 2-chlorodeoxyadenosine in mouse FM3A cells was investigated. Imbalance of the dNTP pools occurred within 3 h of treatment with 20 µM 2-chlorodeoxyadenosine; the dATP and dGTP pools were depleted and the dTTP pool increased. 2-Chlorodeoxyadenosine added to the culture medium broke mature DNA strands, giving fragments of 100–200 kilobase pairs as found by orthogonal-field-alternation gel electrophoresis. DNA strand breaks, measured by this technique, were observed in the treated cells about 12 h after the addition. The cells also lost viability at about 12 h. Breaks in the single and double strands of DNA, as measured by alkaline and neutral filter elution, became evident 18 h after treatment with 20 µM 2-chlorodeoxyadenosine; there were as many single-strand breaks as would be caused by 130 rads of -ray irradiation. Double-strand breaks were equivalent to those caused by 2180 rads of -ray irradiation. Comparison of the ratio of single- and double-strand breaks caused by 2-chlorodeoxyadenosine to that following radiation suggested that 2-chlorodeoxyadenosine broke only double strands. Cycloheximide inhibited the breakage of DNA double strands and the cell death caused by this compound. Flow cytometric studies of cytostasis brought about by 2-chlorodeoxyadenosine in FM3A cells showed that cells accumulated in the earlier part of the S phase. 2-Chlorodeoxyadenosine decreased DNA synthesis more than RNA or protein synthesis. The breaks in double strands of DNA were probably important in the cell death caused by 2-chlorodeoxyadenosine. The intracellular dNTP imbalance may trigger these events.

¹ Supported in part by grants for scientific research from the Ministry of Education, Science and Culture, Japan (Y. W.)

² To whom requests for reprints should be addressed.

Received 4/ 8/88. Revised 9/21/88. Accepted 11/ 2/88.

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