| Description | Discovered in 1875, gallium is a trivalent metal that shares certain chemical characteristics with Fe 3+, Al3+ and In3+. An important property of gallium is its high affinity binding to transferrin, the iron transport protein in the circulation. Approximately one third of transferrin in blood is occupied by iron, leaving the remainder free to bind and transport gallium to cells that display transferrin receptors. In support of this mechanism is the finding that during radiogallium tumor imaging (Ga-67 scanning) in patients, Ga-67 in the circulation is bound almost exclusively to transferrin. A recent study examining the distribution of nonradioactive gallium in the circulation after its gastrointestinal uptake from gallium maltolate (an oral formulation of gallium) has confirmed that it binds to transferrin. The cellular uptake of gallium (transferrin-gallium) is mediated primarily by cell surface transferrin receptors, although a small amount of gallium may also be incorporated into cells via transferrin dependent mechanisms. Transferrin receptors are normally present on erythroid progenitor cells in the marrow to facilitate cellular iron uptake for hemoglobin synthesis. However, transferrin receptors are also expressed in high density on proliferating cells, because iron is needed for the activity of ribonucleotide reductase, the enzyme responsible for deoxyribonucleotide synthesis. In particular, transferrin receptors are expressed on non Hodgkin lymphoma (NHL) and bladder cancer cells (but not on their normal counterparts), making them obvious targets for gallium. Although the transferrin mediated delivery of gallium to cancer cells appears to be an important initial step in its antineoplastic action, the downstream events leading to cell death are only partly understood. At the cell surface, transferrin gallium competes with transferrin iron for entry into the cell. Inside the cell, endosomal acidification, essential for the release of iron from transferrin, is perturbed by gallium. Hence, gallium disrupts cellular iron homeostasis. The gallium induced block in cellular iron uptake, coupled with a direct effect of intracellular gallium, leads to inhibition of the iron-dependent R2 subunit of ribonucleotide reductase and an arrest in DNA synthesis. The nature of gallium-induced cell death was first reported by Haq et al. who demonstrated the induction of DNA fragmentation and morphologic changes consistent with apoptosis in lymphoma cells exposed to gallium nitrate. More recently, gallium nitrate was shown to induce apoptosis through the intrinsic pathway involving Bax, mitochondrial release of cytochrome c, and caspase-3 activation. The molecular basis for tumor cell resistance to gallium is not understood. It is not the result of an increase in ribonucleotide reductase activity, but it may be related to decreased cellular gallium incorporation. A complementary DNA microarray analysis of gallium resistant and gallium sensitive lymphoma cell lines has suggested that gallium resistance may involve changes in proteins responsible for intracellular trafficking. The action of gallium extends to other pathologic conditions in which cellular transferrin receptors are increased. Mitogen activated T and B cells express transferrin receptors; the proliferation of these cells, along with immunoglobulin production by B cells, can be inhibited by gallium. Gallium nitrate has been shown to have immunosuppressive activity in animal models of graft-versus-host disease following bone marrow transplantation, adjuvant arthritis, cardiac transplant rejection, and allergic autoimmune encephalomyelitis. 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-Hodgkin's lymphoma. (PMID: 15579097 , 15627016 ) |
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