Gallium Nitrate

Gallium Nitrate is one of the Group Ilia "near-metal" salts originally evaluated for antineoplastic activity by researchers at the National Cancer Institute during a full screening of all elements of the periodic table. When initially examined by Hart and colleagues, gallium was found to be the most active of the Group IIIa elements, inhibiting greater than 90% tumor growth in six of eight subcutaneous solid tumors tested in rodents, but less effect on leukemia.57,58 Later, phase I and phase II studies demonstrated the adverse effect of hypocalcemia, which led to FDA approval in the United States for the use of gallium nitrate for cancer-related hypercalcemia. Gallium has further been tested with encouraging results in patients with lymphoma, multiple myeloma,59 uroepithelial cancer,60 and ovarian cancer.61 The kinetics of gallium were initially established by Hall and colleagues in 1971.62 The initial half-life was 1 h, volume of distribution approximated total body water, and approximately 94% was excreted in the urine in the first 24 h.

A number of mechanisms have been proposed for the antineoplastic activity of gallium, including cellular deprivation of ferric iron by transferrin-dependent inhibition, inhibition of ribonucleotide reductase, induction of apoptosis, and interference with protein tyrosine phosphatases. Gallium binds to transferrin, although at lower affinity than iron, forming a Ga-Tf complex. It is well established that lymphoma cells express an increased number of transferrin receptors.63 By absorbing Ga3+ instead of Fe3+, the cell up-regulates transferrin receptors, and therefore permits more incorporation of gallium into the cell. This inevitably starves the cell of iron, which may lead to cell death. There is also evidence that the Ga-Tf complex inhibits the intracellular release of iron, further leading to the iron deprivation.64 This intracellular inhibition was found in vitro to be reversible by transferrin-iron complex, iron salts, or hemin.

A second mechanism of gallium is its interaction with ribonucleotide reductase. Chitambar et al.65 demonstrated in L1201 leukemia cells that although inhibition of iron uptake indirectly inhibits the ribonucleotide reductase M2 subunit, gallium had a direct effect on the enzyme as well by inhibition of cytosine diphosphate (CDP) or (ADP). Further studies showed this interaction between gallium and ribonucleotide reductase was synergistic with hydroxyurea, a drug that also interacts with the M2 subunit of ribonucleotide reductase.66

Initial studies with gallium nitrate in lymphoma involved bolus administration at a dose of 700 mg/m2 every 2 weeks.67'68 The response rate was low (18%) and the toxicities included gastrointestinal toxicity, reversible renal insufficiency, and anemia. To decrease renal toxicity, Warrell et al. administered gallium nitrate by continuous 24-h i.v. infusion for 7 days every 3-5 weeks at doses of 200-400 mg/m2 (Ref. 69). The maximum tolerated dose, defined by renal insufficiency, was 400 mg/m2/day. In the phase II study,69 47 patients who had previously failed conventional chemotherapy and who had bidimensionally measurable disease were evaluated. The patient population had a median of three prior therapies and many had extranodal involvement. The overall response rate was 34% (10% for Hodgkin's lymphoma and 43% for NHL patients), with two complete responses. The median duration of response was 2.5 months.

A further trial evaluated mitoguazone 600 mg/m2 i.v. on days 1 and 10, etoposide 100-125 mg/m2 i.v. on days 2-4, and continuous i.v. gallium nitrate on days 1-7, given every 3-4 weeks.70 The patient population ranged from 19-77 years, with a median of two prior therapies and all had stage III or IV disease. The overall response rate was 52% but was higher (69%) for patients with diffuse large cell lymphoma. The toxicity of this regimen, however, was significant. Eighteen patients (42%) developed neutropenic fevers and three died. Other toxicities included mucositis (47%), keratitis and conjunctivitis (26%), diarrhea (21%), renal toxicity (16%), and optic neuritis (12%), which caused transient blindness in three of the five patients affected.

A third combination regimen with gallium was based on the in vitro studies demonstrating synergy between gallium and hydroxyurea.71 Chitambar and colleagues evaluated 14 patients with stage III or IV low- or intermediate-grade, refractory lymphoma. The age range was 53-80 years, with a median of three treatments and a median of six previous agents. Patients received doses of 200, 250, 300, or 350 mg/m2 i.v. continuous infusion gallium for 7 days with either 500 mg or 1000 mg hydroxyurea concomitantly. Six of the 14 patients (43%) had a response, and the median response duration was 7 weeks. Further studies are underway to define the activity of gallium nitrate in patients with lymphoma.

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