Mechanisms of action

The mechanisms for the observed therapeutic activities of gallium have been reviewed,9 so will be only briefly summarized here.

Much of gallium's therapeutic activity derives from its ability to mimic Fe3+ and yet not to participate in the redox reactions available for Fe3+. This mimicry leads to the concentration of gallium at sites in the body where Fe3+ is taken up from plasma, including proliferating cancer cells; infected cells, particularly macrophages; and proliferating bacteria and parasites. When gallium reaches these sites it will compete with Fe3+ and will interfere with its absorption, metabolism and activity.

Iron is essential to cell division, largely because it is present in the active site of ribonucleotide reductase, an enzyme that catalyzes the production of the deoxy-ribonucleotides required for DNA. By competing with iron, gallium can interfere with ribonucleotide reductase activity and inhibit DNA synthesis.51 Furthermore, Ga3+ can substitute for Fe3+ in the M2 subunit of ribonucleotide reductase, deactivating the enzyme through a conformational change.52,53 If DNA synthesis is inhibited in proliferating cells, apoptosis may result: in human leukemic CCRF-CEM cells deprived of iron, by exposure to either deferoxamine or 12.5-100 mM gallium nitrate, apoptosis is induced.54 Similarly, exposure of human peripheral blood mononuclear cells to 50-100 mM gallium nitrate induces apoptosis.55

Cancer cells that take up gallium become iron-deprived, which causes upregu-lation of TFR1.56 Increased TFR1 promotes increased Ga-TF uptake, leading to increased iron deprivation, and this cycle continues until apoptosis of the cell results. Ga-TF may cause additional iron deprivation by preventing sufficient acidification of Fe-TF-containing endosomes to allow for the intracellular release of Fe.56

Several in vitro studies57,58 have found that Ga3+ can directly bind to DNA, and may compete with magnesium in this regard. As these studies were done using isolated DNA at pH values of 4 5, their relevance to in vivo gallium activity is not clear.

Gallium nitrate and Ga-TF were found to potently inhibit protein tyrosine phosphatase (PTPase) from Jurkat human T-cell leukemia cells and HT-29 human colon cancer cells (IC50 value of 2-6 mM).59 This activity did not, however, correlate with growth inhibition in these cells, and a relationship between the observed PTPase inhibition and gallium's anti-tumor activity has not been established.

As mentioned, gallium inhibits the proliferation of some pathogenic microorganisms. It may be particularly effective in treating some intracellular pathogens, such as species of Mycobacterium.60 Infected cells (particularly macrophages) take up Ga-TF; the infecting organisms then take up gallium instead of iron and, as with cancer cells, cannot synthesize sufficient DNA for replication, and ultimately die.

In addition to these anti-proliferative activities, gallium is potently anti-resorptive to bone mineral, appears to have anabolic (formation-stimulating) effects on bone, inhibits some T-cell and macrophage activation and has other selective immunomodulatory activities.9

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