EVALUATION OF TRANSFERRIN AND GALLIUM-PYRIDOXAL ISONICOTINOYL HYDRAZONE AS POTENTIAL THERAPEUTIC AGENTS TO OVERCOME LYMPHOID LEUKEMIC-CELL RESISTANCE TO GALLIUM NITRATE

Gallium nitrate is active against lymphoma and bladder cancer; however , little is understood about tumor resistance to this drug, Transferri n, the iron transport protein, increases gallium uptake by cells, wher eas pyridoxal isonicotinoyl hydrazone (PIH), an iron chelator, transpo rts iron into cells, Therefore, we examined whether these metal transp orters would increase the cytotoxicity of gallium in gallium nitrate-r esistant CCRF-CEM cells, Transferrin, in increasing concentrations, en hanced the cytotoxicity of gallium nitrate, One mg/ml transferrin decr eased the 50% inhibitory concentration of gallium nitrate from 1650 to 75 mu M in gallium-resistant cells and from 190 to 150 mu M in galliu m-sensitive cells, Transferrin also enhanced the cytotoxicity of galli um even at drug concentrations that were not growth inhibitory, The ga llium chelate Ga-PIH inhibited the growth of both gallium nitrate-resi stant and -sensitive cells, Fifty mu M Ga-PIH inhibited cellular proli feration by 50%, whereas similar concentrations of PIH or gallium nitr ate were not growth inhibitory, However, because higher concentrations of PIH also inhibited cell growth, the cytotoxicity of Ga-PIH was gre ater than PIH only at concentrations of < 100 mu M. Cross-titration ex periments demonstrated that the cytotoxicity of PIH was partially reve rsed by gallium nitrate, whereas the cytotoxicity of gallium nitrate w as enhanced by PIH, Our studies suggest that Ga-PIH warrants further e valuation as a potential antineoplastic agent, Because transferrin inc reases the cytotoxicity of gallium nitrate in transferrin receptor-bea ring, gallium nitrate-resistant cells, future clinical trials of this drug should incorporate the development of strategies to increase plas ma transferrin levels.