Faculty Collaboration Database

Interaction of gallium nitrate with fludarabine and iron chelators: effects on the proliferation of human leukemic HL60 cells. Cancer Res 1990 Oct 15;50(20):6466-70

Date

10/15/1990

Pubmed ID

1698536

Scopus ID

2-s2.0-0025146833 (requires institutional sign-in at Scopus site)   42 Citations

Abstract

Earlier studies have shown that transferrin-gallium inhibits cellular iron incorporation and blocks DNA synthesis by decreasing the activity of the iron-dependent M2 subunit of ribonucleotide reductase. We examined the growth-inhibitory effects of gallium nitrate in combination with clinically relevant inhibitors of ribonucleotide reductase fludarabine (an M1 subunit inhibitor), and iron chelators (M2 subunit inhibitors). Fludarabine and gallium nitrate in combination produced a significant increase in cell growth inhibition when compared with either agent alone; however, this effect was partially reversible up to 24 h and was best seen with continuous exposure of cells to both drugs. Incubation of cells with desferrioxamine and gallium nitrate resulted in reversal of gallium-induced growth inhibition. Incubation of cells with N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid and gallium nitrate resulted in a slight increase in gallium-induced growth inhibition, with partial restoration of cell growth occurring only at a single high concentration of N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid. Both chelators inhibited 67Ga uptake by cells and increased cell surface transferrin receptors. In contrast to the coincubation studies, sequential exposure of cells to desferrioxamine or N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid and gallium nitrate resulted in a significant potentiation of the growth-inhibitory effects of gallium nitrate. Our studies show that cellular iron deprivation results in enhanced sensitivity of cells to gallium. Furthermore, the combined effects of fludarabine and gallium on cell growth may be of clinical relevance, since both agents are active against lymphoid cancers.

Author List

Lundberg JH, Chitambar CR

Author

Joel Lundberg MD Adjunct Assistant Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents
Cell Division
Deferoxamine
Drug Synergism
Edetic Acid
Gallium
Humans
Iron
Iron Chelating Agents
Leukemia, Promyelocytic, Acute
Tumor Cells, Cultured
Vidarabine Phosphate