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Thioguanine-induced S and G₂ Blocks and Their Significance to the Mechanism of Cytotoxicity

College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109 [L. L. W.], and Department of Radiology, College of Medicine, University of Utah, Salt Lake City, Utah 84132 [J. L. R. R.]

The delayed cytotoxic effect of 6-thioguanine (TG) was studied using L1210 mouse leukemic cells in culture. The cell cycle distribution of a population treated continuously with 10^-5 M TG was compared to that of control cells using flow cytometric analysis. The TG-treated cells had an increase in the fraction of the population in G₂-M, a decrease in G₁, and a constant level in S phase. However, the [methyl-³H]thymidine-labeling index decreased dramatically during TG treatment. Thus, it appeared that some cells were arrested in S phase and that G₁ cells did not enter S phase, due to failure to synthesize DNA. To examine the importance of the G₂ and S cell progression blocks, cells were exposed to a lethal treatment of 10^-5 M TG for 12 hr and returned to normal medium. Under these conditions, the fraction of the population in both S and G₁ decreased, and nearly one-half of the cells accumulated in G₂ by 60 hr after TG addition, compared to a G₂ fraction of less than one-tenth for the control cells. These results showed that the delayed cytotoxic effect of TG was associated with a cell progression block in the second G₂ phase after TG addition, whereas the retention of cells in S phase appeared to be due to readily reversible secondary effects of TG.

¹ Supported in part by an allocation while in the Department of Biochemical Pharmacology and Toxicology, College of Pharmacy, University of Utah, from an American Cancer Society Institutional Research Grant IN-102B to the University of Utah. To whom requests for reprints should be addressed.

² Supported by Research Career Development Award, CA00234 awarded by the National Cancer Institute, Department of Health, Education, and Welfare.

Received 5/14/79. Accepted 1/29/80.

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