Gallium nitrate for the treatment of non-Hodgkin’s lymphoma

Abstract

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.

Inhibition of the Proteasome Activity by Gallium(III) Complexes Contributes to Their Anti–Prostate Tumor Effects

“…It has also shown efficacy against a diverse set of disorders such as accelerated bone resorption and autoimmune and infectious diseases (2). Gallium is currently approved for the treatment of hypercalcemia associated with malignancy (7)(8)(9). Besides its therapeutic utility, for over a half century, Ga 67 has been used as a diagnostic agent for cancer (5,10).…”

Chelators at the Cancer Coalface: Desferrioxamine to Triapine and Beyond

“…To attain more Fe, neoplastic cells express higher levels of the transferrin receptor 1 (TfR1) and take up Fe at a greater rate than their normal counterparts (1). This is reflected by the ability of tumors to be radiolocalized using 67 Ga, which binds to the Fe transport protein, transferrin, for delivery via TfR1 (3,4). Similarly, phosphorothiolated antisense TfR1 oligonucleotides targeted to TfR1 mRNA showed selective anticancer activity (5), confirming the importance of Fe in cancer cell growth.…”

Development of Gallium Compounds for Treatment of Lymphoma: Gallium Maltolate, a Novel Hydroxypyrone Gallium Compound, Induces Apoptosis and Circumvents Lymphoma Cell Resistance to Gallium Nitrate

“…Hence, there remains a great need to develop novel agents for the treatment of this malignancy. In the late 1970s, the group IIIa metal salt gallium nitrate was discovered to have antitumor activity in animal tumor models, and in subsequent clinical trials, it proved to have significant antineoplastic activity against non-Hodgkin's lymphoma and urothelial malignancies (Warrell et al, 1983;Weick et al, 1983;Keller et al, 1986;Einhorn, 2003;Chitambar, 2004). A more recent clinical trial confirmed the efficacy of gallium nitrate in patients with nonHodgkin's lymphoma whose disease had relapsed following treatment with conventional chemotherapeutic agents (Pro et al, 2004).…”