title: Hydroxyurea-induced cell death in human T lymphoma cells as related to imbalance in DNA/protein cycle and deoxyribonucleotide pools and DNA strand breaks.
abstract: The aim of this study was to elucidate the mechanism(s) behind the cellular toxicity of therapeutic concentrations of hydroxyurea (HU). Treatment of human T lymphoma cells (CCRF-CEM) with 60-100 microM of HU for 24 h decreased the growth rate by 90% due to accumulation of cells in early S phase. It induced a marked imbalance in both the DNA/protein cycle (as measured by two-parameter flow cytometry) and the deoxyribonucleotide (dNTP) pools. HU treatment did not enhance the frequency of DNA single-strand breaks (SSBs), as measured by the alkaline unwinding technique. Cell viability was unaffected. However, removal of HU led to 10-15% cell loss during the following 12 h period in parallel with increasing SSBs, and a rapid progression of cells through S and G2 stages. The unbalanced DNA to protein content per cell and the dNTP pools were normalized 6-12 and 24 h after removal of HU, respectively. These results show that marked changes in the DNA to protein ratio and dNTP pools alone are not directly lethal, but when combined with a high replicative DNA synthesis rate, as found after removal of HU, apparently lead to elevated cell death.
authors.affiliation: Department of Medical Radiobiology, Karolinska Institute, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Skog
authors.forename: T
authors.initials: T
authors.lastname: Heiden
authors.forename: S
authors.initials: S
authors.lastname: Eriksson
authors.forename: B
authors.initials: B
authors.lastname: Wallström
authors.forename: B
authors.initials: B
authors.lastname: Tribukait
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage / Q000502:physiology*; D004273:DNA, Neoplasm / Q000187:drug effects*; D003853:Deoxyribonucleosides / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D016399:Lymphoma, T-Cell / Q000188:drug therapy*; D009363:Neoplasm Proteins / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D003853:Deoxyribonucleosides; D003854:Deoxyribonucleotides; D009363:Neoplasm Proteins; D006918:Hydroxyurea