SYNERGISTIC INHIBITION OF T-LYMPHOBLASTIC LEUKEMIC CCRF-CEM CELL-GROWTH BY GALLIUM AND RECOMBINANT HUMAN ALPHA-INTERFERON THROUGH ACTION ONCELLULAR IRON UPTAKE

Gallium, a metal with clinical antineoplastic activity, is known to in hibit cellular iron uptake and iron-dependent DNA synthesis. Little in formation exists regarding the efficacy of gallium in combination with other agents. Since alpha-interferon (IFN-alpha) can modulate the act ion of certain chemotherapeutic drugs, me examined its influence on th e growth inhibitory effects of gallium in CCRF-CEM cells. IFN-alpha an d gallium as single agents had only minimal to moderate antiproliferat ive effects. In combination, however, both drugs synergistically inhib ited cell growth, causing cell death accompanied by DNA fragmentation. At lower concentrations (120 mu M), gallium inhibited cellular iron u ptake but did not increase transferrin receptor expression, nor did it block cellular proliferation. The addition of IFN-alpha to this conce ntration of gallium significantly increased the gallium-induced block of iron uptake, resulting in an increase in transferrin receptors and an inhibition of cell growth. In contrast, IFN-alpha did not enhance t he effects of the iron chelator deferoxamine on iron uptake or cell gr owth. Our studies suggest that gallium and IFN-alpha synergistically i nhibit DNA synthesis through a mechanism that includes inhibition of c ellular iron uptake and depletion of intracellular iron below the crit ical level needed to maintain DNA synthesis.