Gallium and other main group metal compounds as antitumor agents

Gallium has been the second metal to show activity against malignant tumors in humans soon after the establishment of platinum drugs in routine clinical practice. It has the unique property of inhibiting tumor growth as a simple cation, mainly because of its close resemblance to ferric iron. Even though its inability to shift between the trivalent and a divalent oxidation state precludes that gallium behaves as an iron analogue in every respect, it strongly interferes with cellular acquisition of iron from blood by competitive interaction with transferrin and transferrin receptor-mediated endocytosis. Furthermore, gallium also seems to affect intracellular availability of iron already taken up via this pathway, probably due to its inhibitory activity on vacuolar-type H(+)-ATPases. Apart from the consequences of iron deprivation, gallium exerts cytotoxic effects by direct interaction with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis. Both the abundance of transferrin receptors and upregulation of ribonucleotide reductase render tumors susceptible to gallium-induced cytotoxicity. However, some experimental findings raise the question whether these effects resulting from the iron-mimicking properties of gallium are solely responsible for its antineoplastic activity or whether additional mechanisms are involved, such as antimitotic effects which result from its capability of inhibiting tubulin polymerization. The limitations experienced with gallium nitrate and gallium chloride, which call for a prolonged exposure to low steady-state gallium levels in blood in order to adequately exploit the affinity of gallium to tumor tissues and to avoid severe toxic effects, may be overcome by oral gallium complexes such as tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) or tris(8-quinolinolato)gallium(III) (KP46), which are currently being evaluated in clinical trials and show promise to initiate a revival of gallium in the clinical setting. These two investigational drugs, albeit differing in their complex stability, have both been developed with the intention of providing gallium in a form which allows sufficient intestinal absorption, but without altering its pharmacodynamic effects. Gallium complexes based on other rationales are scarce and, with regard to the well-known antineoplastic potential of this metal, noticeably under-explored. With the recent approval of arsenic trioxide for the second-line treatment of acute promyelocytic leukemia, the clinical revival of arsenic compounds, which have been the mainstay of antileukemic therapy before the age of modern cancer chemotherapy, has already begun. Currently, strong efforts are being made to explore the activity spectrum in other (less rare) malignancies and to gain a deeper insight into the mode of action. Although this development is currently focusing on arsenic trioxide, it should be suited to stimulate investigations into the therapeutic potential of other arsenic compounds as well.