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Cell Cycle Synchronization and Growth Inhibition by 3-Hydroxypyridin-4-one Iron Chelators in Leukemia Cell Lines¹

Department of Haematology, University College and Middlesex School of Medicine [K. P. H., J. B. P.], and the Department of Pharmaceutical Chemistry, Kings College [R. C. H.] London, United Kingdom

The effect of bidentate 3-hydroxypyridin-4-one (HPO) iron chelators on cell cycle arrest with subsequent cycle synchronization has been compared with that of the hexadentate desferrioxamine (DFO) in K562 and Daudi cells. The relationships between chelator concentration and inhibition of growth, DNA synthesis and ribonucleotide reductase, and phase of cell cycle arrest have also been explored. HPOs and DFO arrest the cell cycle in a dose-dependent manner causing a blockade at the G₁-S border after 24 h at concentrations above 30 µM iron-binding equivalents. This is associated with reduced ribonucleotide reductase activity and concomitant cessation of DNA synthesis and growth. When the chelator is subsequently removed, HPO-treated cells synchronously cascade into S phase, unlike DFO-treated cells which resume cycling in a nonsynchronous manner. Chelator concentrations of approximately 25 µM and 3 µM iron-binding equivalents inhibited growth, DNA synthesis, and ribonucleotide reductase activity by 50% in K562 and Daudi cells, respectively. Concentrations less than 10 µM iron-binding equivalents inhibited K562 cell growth without an effect on DNA synthesis but with accumulation of cells in G₂ and M phases. These results suggest that HPOs have advantages over DFO as cell cycle synchronization agents and may be useful adjuncts in cell cycle-specific treatment regimens.

¹ The work is supported by the National Institutes of Health Grant RO1-HL-42800-01.

² Present address: Department of Experimental Radiation Oncology, Paterson Institute for Cancer Research, Wilmslow Road, Manchester M20 9BX, United Kingdom.

³ To whom requests for reprints should be addressed, at Department of Haematology, University College and Middlesex School of Medicine, 98 Chenies Mews, London WC1E 6HX, United Kingdom.

Received 5/17/91. Accepted 6/18/92.

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