Abstract
The association between DNA precursor synthesis, cell cycle perturbations, and cell death caused by the anticancer drug hydroxyurea was investigated in mouse and human T-lymphoma cells. Hydroxyurea inhibits the enzyme ribonucleotide reductase, leading to decreased deoxyribon-ucleoside triphosphate pools and an accumulation of cells in early S-phase of the cell cycle. We wished to clarify the mechanism of cell death caused by hydroxyurea in concentrations that can be obtained therapeutically.
At a 60-µm concentration of the drug, giving 25% growth inhibition during 24 h, no increase in the number of dead cells was observed as determined by cell flow calculations and density gradient centrifugation. However, the removal of hydroxyurea led to 10–30% cell loss during the following 12-h period. In parallel, there was an increase in DNA precursor levels and a rapid progression of cells through S- and G2 phases of the cell cycle. The isolated dead cells showed no overrepresentation of any cell cycle phase.
The results demonstrate that, although the toxic effects of low concentrations of hydroxyurea are minimal, the drug-induced unbalanced growth state can cause substantial cell death during a posttreatment period.
Footnotes
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↵1 This work was supported by grants from the Swedish Medical Research Council, the Swedish Cancer Society, the Medical Faculty of the Karolinska Institute, and the Cancer Society of Stockholm.
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↵2 To whom requests for reprints should be addressed, at Karolinska Institutet, Department of Biochemistry I, P. O. Box 60400, S-104 01, Stockholm, Sweden.
- Received March 30, 1987.
- Revision received July 22, 1987.
- Accepted August 26, 1987.
- ©1987 American Association for Cancer Research.
Volume 47, Issue 24 Part 1
