Gallium nitrate for the treatment of non-Hodgkin's lymphoma.

Mortality from non-Hodgkin's lymphoma (NHL) is high, thus defining the need for additional therapeutic agents for this disease. Gallium nitrate is a metal compound that is presently approved for the treatment of hypercalcaemia associated with malignancy. In clinical trials first conducted over two decades ago, this drug was found to have antineoplastic activity in NHL. However, its development as an antineoplastic agent for the treatment of NHL was never rigorously pursued. Gallium has unique mechanisms of action that include its binding to transferrin in the circulation and targeting transferrin receptors present on lymphoma cells. As it shares chemical properties with iron, gallium can disrupt critical steps in iron homeostasis that are essential for tumour cell viability and growth and can inhibit the iron-dependent activity of ribonucleotide reductase. The drug may also target other cellular processes unrelated to iron. Phase I/II studies have shown that gallium nitrate displays the most efficacy and lowest toxicity in NHL when administered as a continuous intravenous infusion, producing response rates of 43% in patients with relapsed or refractory NHL. It does not suppress the white blood cells or platelets and does not share cross-resistance with other chemotherapeutic drugs. These characteristics make it particularly attractive for the treatment of myelosuppressed patients and for incorporation into combination therapy. Multi-institutional Phase II clinical trials are in progress to evaluate gallium nitrate as a single agent or in combination. These studies will help define its role in the current treatment of NHL.