Apoptotic Mechanisms of Gallium Nitrate: Basic and Clinical Investigations
November 04, 2004
Gallium nitrate inhibits the growth of various lymphoma cell linesin vitro and exhibits antitumor activity in patients with lymphoma.The mechanism(s) of cytotoxicity is (are) only partly understood butappears to involve a two-step process: (1) targeting of gallium to cells,and (2) acting on multiple, specific intracellular processes. Galliumshares certain chemical properties with iron; therefore, it binds avidlyto the iron transport protein transferrin. Transferrin-gallium complexespreferentially target cells that express transferrin receptors on theirsurface. Expression of transferrin receptors is particularly high onlymphoma cells. Cellular uptake of the gallium-transferrin complexleads to inhibition of cellular proliferation primarily via disruption ofiron transport and homeostasis and blockade of ribonucleotidereductase. Recent studies have shown that cellular uptake of galliumleads to activation of caspases and induction of apoptosis. In phase IItrials in patients with relapsed or refractory lymphoma, the antitumoractivity of gallium nitrate is similar to, or better than, that of othercommonly used chemotherapeutic agents. Gallium nitrate is notmyelosuppressive and may be used in patients with neutropenia orthrombocytopenia. A multicenter trial to evaluate the use of galliumnitrate in patients with relapsed non-Hodgkin's lymphoma is currentlyongoing.