The trivalent gallium cation is capable of inhibiting tumor growth, mainly because of its resemblance to ferric iron. It affects cellular acquisition of iron by binding to transferrin, and it interacts with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis. The abundance of transferrin receptors and the up-regulation of ribonucleotide reductase render tumor cells susceptible to the cytotoxicity of gallium. Remarkable clinical activity in lymphomas and bladder cancer has been documented in clinical studies employing intravenous gallium nitrate, which is currently being re-evaluated in non-Hodgkins lymphoma. An improved therapeutic index is expected to result from prolonged exposure to low steady-state plasma gallium levels. Attempts to accomplish this by oral administration of gallium chloride failed because of insufficient intestinal absorption. Complexation of gallium with ligands, which stabilize gallium against hydrolysis and facilitate membrane permeation, has been recognized as a promising strategy for overcoming these limitations. Two such gallium complexes, namely tris(3-hydroxy-2-methyl- 4H-pyran-4-onato)gallium(III) (gallium maltolate) and tris(8-quinolinolato)gallium(III) (KP46), which both exhibit high bioavailability when administered via the oral route, are currently being evaluated in the clinical setting.
Keywords: gallium nitrate, gallium chloride, gallium maltolate, kp, iron(III), transferrin binding, ribonucleotide reductase, oral bioavailability
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