Gallium-pyridoxal isonicotinoyl hydrazone (Ga-PIH), a novel cytotoxic gallium complex. A comparative study with gallium nitrate.

The anti-proliferative activity of gallium-pyridoxal isonicotinoyl hydrazone (Ga-PIH), a novel gallium complex was compared with that of gallium nitrate, a known anti-tumor agent. At 50 microM, Ga-PIH inhibited CCRF-CEM cell growth by 45% compared to < 10% inhibition with gallium nitrate or PIH. The IC50s for Ga-PIH, gallium nitrate and PIH were 60, 84 and 68 microM respectively. The addition of exogenous iron as transferrin-iron to the culture medium reversed the cytotoxicity of gallium nitrate and PIH in a dose-dependent manner but had only minor effects on the cytotoxicity of Ga-PIH. The effect of these compounds on cellular iron uptake was measured since prior studies have shown that gallium perturbs iron transport into cells. Fifty micromolar Ga-PIH, gallium nitrate or PIH inhibited the cellular uptake of 59Fe-transferrin over 24 h by 65%, 32%, and 78% respectively. Although all three compounds inhibited iron uptake, only Ga-PIH produced a significant upregulation of cellular transferrin receptors. Since the cytotoxicity of Ga-PIH appears to be less influenced by extracellular iron and cellular transferrin receptor expression, it may have potential as an antineoplastic agent and should be further evaluated in animal tumor models.