Tumor cell toxicity of stable gallium nitrate: enhancement by transferrin and protection by iron.

The cytotoxicity of citrated gallium nitrate (NSC 15200) to EMT-6/UW mouse sarcoma cells growing in vitro was assayed as growth inhibition in treated cultures as well as cell survival (colony-forming ability) after acute or chronic exposure to graded doses. Gallium nitrate is both cytostatic and lethal to cells, with some growth inhibition occurring after chronic exposure to low doses (10 micrograms/ml) which kill essentially no cells. Cell kill and growth inhibition were both observed if cells were exposed for 24 hr or more to doses greater than 50 micrograms/ml. The growth inhibitory and lethal effects of gallium nitrate were enhanced by the addition of human transferrin to the medium. This enhanced toxicity was consistent with, and proportional to, the increased gallium uptake in the presence of transferrin rather than a direct effect of this iron transport protein. The addition of ferric citrate greatly reduced the toxic effect of the gallium salt. Cells in stationary plateau phase cultures appear to be as sensitive to gallium nitrate as exponentially growing cells. Ga3+ may mimic Fe3+ in some aspects of cellular metabolism, and competition between the two metals occurs at the initial uptake step, binding to transferrin, and possibly at other points in cell metabolism.