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.