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PubMedDate not supplied

Sensitizing effects of gallium citrate on hyperthermic cell killing in vitro.

The lethal effects of gallium citrate in combination with heat were studied using four cell lines, L5178Y, FM3A, P388 and HeLa. Cells were incubated with different concentrations (0.2 2 mM) of gallium citrate at 37 degrees C for 24 h and heated at a range of temperatures from 40-44 degrees C for various time periods up to 6 h in the absence of gallium citrate. Survival and cell viability were determined by clonogenic assay and the dye-exclusion test, respectively. All of the cell lines tested were insensitive to heat below 41 degrees C, but were very sensitive to heat above 43 degrees C. Gallium citrate was cytotoxic to these cell lines at different levels: P388 and HeLa were far more sensitive than L5178Y and FM3A. The killing effects of heat at 41 degrees C were greatly enhanced by gallium citrate in L5178Y and P388 cells. The Arrhenius analysis for the lethal effect of heat, determined by clonogenic assay, in L5178Y cells showed that the transition temperature was remarkably decreased for the gallium-treated cells from approximately 43 degrees C to 41 degrees C. The mechanism for this decrease in the transition temperature may be attributable to the additional effects of gallium citrate on energy metabolism. Preincubation with 0.05 mM gallium citrate at 37 degrees C for 7 days also enhanced heat sensitization at 41 degrees C in L5178Y. This preincubation condition may correspond to the condition for the continuous infusion of gallium that is clinically used for cancer treatment. In contrast, treatment with gallium did not greatly enhance the sensitivity of FM3A or HeLa cells to heat at 41 degrees C, but the effects of gallium were significant.

Adenosine Triphosphate↗
PubMed1993

Low-dose gallium nitrate for prevention of osteolysis in myeloma: results of a pilot randomized study.

PURPOSE: Since osteolysis is a major cause of morbidity in myeloma, we conducted a pilot study to evaluate whether the addition of gallium nitrate to standard antimyeloma treatment could preserve or increase bone mass in patients with osteolytic disease. METHODS: Patients stabilized on cytotoxic therapy were randomized to treatment with gallium nitrate for 6 months, or to observation only for the first 6 months followed by gallium nitrate treatment during the subsequent 6 months. Gallium nitrate was administered in monthly cycles by daily subcutaneous injections (30 mg/m2/d) for 2 weeks, followed by 2 weeks with no therapy, supplemented by an intravenous infusion (100 mg/m2/d) for 5 days every other month. RESULTS: Paired 6-month comparisons were available for seven observation periods and 13 gallium nitrate treatment periods. Total-body calcium assessed by delayed-gamma neutron activation (DGNA) decreased in four of seven patients during observation, but increased in nine of 13 patients during gallium nitrate treatment; the mean difference in total-body calcium (TBCa) between the two groups at 6 months was 3%. Median regional bone density assessed by dual-photon absorptiometry (DPA) declined by 1.4% in patients under observation (range, +6.7% to -18.3%), but was unchanged during gallium nitrate treatment (median change, 0%; range, -10.5% to +14.4%). The group mean vertebral fracture index assessed by lateral spine x-rays decreased by 27% during observation compared with 2% during gallium nitrate treatment. Mean body height decreased by 0.57 inches in the observation group and .06 inches in the gallium nitrate group. Patient self-assessment of bone pain showed that seven of 12 gallium nitrate-treated patients rated themselves as experiencing major reductions in bone pain, compared with zero of seven patients who were observed. One episode of hypercalcemia occurred in a patient under observation. CONCLUSION: Adjuvant treatment with low-dose gallium nitrate attenuates the rate of bone loss in myeloma and may be useful for ameliorating the consequences of skeletal morbidity in patients with cancer-related osteolysis.

Adult↗
PubMed2004

Gallium in cancer treatment.

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. An improved therapeutic index is expected to result from prolonged exposure to low steady-state plasma gallium levels. Attempts to accomplish this by oral administration of gallium chloride failed because of insufficient intestinal absorption. Complexation of gallium with ligands, which stabilize gallium against hydrolysis and facilitate membrane permeation, has been recognized as a promising strategy for overcoming these limitations. Two such gallium complexes, namely tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) and tris(8-quinolinolato)gallium(III) (KP46), which both exhibit high bioavailability when administered via the oral route, are currently being evaluated in the clinical setting.

Antineoplastic Agents↗
PubMed1990

Interaction of gallium nitrate with fludarabine and iron chelators: effects on the proliferation of human leukemic HL60 cells.

Earlier studies have shown that transferrin-gallium inhibits cellular iron incorporation and blocks DNA synthesis by decreasing the activity of the iron-dependent M2 subunit of ribonucleotide reductase. We examined the growth-inhibitory effects of gallium nitrate in combination with clinically relevant inhibitors of ribonucleotide reductase fludarabine (an M1 subunit inhibitor), and iron chelators (M2 subunit inhibitors). Fludarabine and gallium nitrate in combination produced a significant increase in cell growth inhibition when compared with either agent alone; however, this effect was partially reversible up to 24 h and was best seen with continuous exposure of cells to both drugs. Incubation of cells with desferrioxamine and gallium nitrate resulted in reversal of gallium-induced growth inhibition. Incubation of cells with N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid and gallium nitrate resulted in a slight increase in gallium-induced growth inhibition, with partial restoration of cell growth occurring only at a single high concentration of N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid. Both chelators inhibited 67Ga uptake by cells and increased cell surface transferrin receptors. In contrast to the coincubation studies, sequential exposure of cells to desferrioxamine or N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid and gallium nitrate resulted in a significant potentiation of the growth-inhibitory effects of gallium nitrate. Our studies show that cellular iron deprivation results in enhanced sensitivity of cells to gallium. Furthermore, the combined effects of fludarabine and gallium on cell growth may be of clinical relevance, since both agents are active against lymphoid cancers.

Antineoplastic Agents↗
PubMed1989

Magnesium alterations and pharmacokinetic data in gallium-treated lung cancer patients.

The dose of gallium chloride required to inhibit tumor growth after oral and chronic administration depends on the stage of the cancer disease and of the type of metastases. A dose regimen of 800 mg/24 h of gallium chloride will provide serum gallium concentrations greater than or equal to 600 micrograms/l in lung cancer patients with a small and limited disease. A dose of 1,400 mg/24 h is well tolerated in metastatic patients but may not be high enough to reach the desired serum gallium concentrations especially in patients with bone metastases. Radiotherapy and/or a chemotherapy will permit one to increase the serum gallium concentrations and the tumor gallium uptake by reducing the volume of the tumor. After chronic, oral administration of gallium a decrease in RBC Mg is noted. To avoid the Mg deficiency, the treatment must not be interrupted and may perhaps be decreased with care and slowly without resulting in a decrease of the serum gallium concentrations provided the treatment has been prolonged over a sufficient time to enable one to induce intratumor biological modifications and a decrease in the number of the malignant cells. Acute pharmacokinetic data are related to the histologic type of the tumor and may not be used to predict the serum gallium concentrations after chronic administration. The serum gallium concentrations required to inhibit the tumor growth may be higher in small cell lung carcinomas than in nonsmall cell lung carcinomas. Frequent Mg and Ga blood determinations are necessary to manage effective gallium treatment.

Administration, Oral↗
PubMed1993

Inhibition of protein tyrosine phosphatase by the antitumor agent gallium nitrate.

Protein tyrosine phosphatases (PTPases) play an important role in regulating cell growth and transformation. We report that the antitumor agent gallium nitrate is a potent inhibitor (concentration producing 50% inhibition, 2-6 microM) of detergent-solubilized cellular membrane PTPase from Jurkat human T-cell leukemia cells and HT-29 human colon cancer cells. This is the first report of a selective, small molecule drug inhibitor of PTPase. Gallium nitrate did not inhibit CD45, a PTPase found in the membranes of hemopoietic lineage cells such as Jurkat cells. Studies with gallium nitrate and a series of gallium-containing analogues revealed no correlation between growth-inhibitory activity in Jurkat and HT-29 cells and the ability to inhibit detergent-solubilized PTPase. Gallium nitrate and most of the gallium analogues penetrate poorly into cells. In contrast, a gallium-hydrogen peroxide complex inhibits DNA synthesis in Jurkat cells and induces the accumulation of phosphotyrosines on multiple intracellular proteins in this cell line. Gallium-hydrogen peroxide complex and gallium nitrate have similar inhibitory activity toward detergent-soluble PTPase. This is a new mechanism of action for gallium nitrate but it is not known if the inhibition of PTPase is related to the antitumor activity of gallium nitrate.

3T3 Cells↗
PubMed1979

Gallium nitrate (NSC-15200) induced toxicity in the rat: a pharmacologic, histopathologic and microanalytical investigation.

Administration of gallium nitrate to rats resulted in the formation of renal precipitates which occluded tubular lumina. When analyzed with a combination of scanning electron microscopy and x-ray energy spectrometry, these precipitates were found to contain gallium complexed with calcium and phosphate. Injection of gallium nitrate also resulted in hypercalciuria, although serum calcium levels remained unaltered. Administration of an osmotic diuretic, isosorbide, prior to gallium treatment resulted in the formation of fewer renal precipitates and histopathologic changes than in the nondiuresed animals. Diuresis did not alter gallium serum pharmacokinetics, the 24 hour cumulative renal excretion of gallium or the extent of the drug-induced hypercalciuria. However, isosorbide pretreatment significantly reduced the urinary concentrations of both gallium and calcium. The data presented indicate that diuresis reduces the severity of gallium-induced renal lithiasis and subsequent renal accumulation of gallium by diluting the urinary concentration of gallium and calcium thereby lowering the incidence of interaction of these two elements within the kidney tubule.

Animals↗
PubMed1993

Gallium nitrate regulates rat osteoblast expression of osteocalcin protein and mRNA levels.

Gallium nitrate, a group IIIa metal salt, has been found to be clinically effective for the treatment of accelerated bone resorption in cancer-related hypercalcemia and Paget's disease. Here we report the effects of gallium nitrate on osteocalcin mRNA and protein levels on the rat osteoblast-like cell line ROS 17/2.8. Gallium nitrate reduced both constitutive and vitamin D3-stimulated osteocalcin protein levels in culture medium by one-half and osteocalcin mRNA levels to one-third to one-tenth of control. Gallium nitrate also inhibited vitamin D3 stimulation of osteocalcin and osteopontin mRNA levels but did not affect constitutive osteopontin mRNA levels. Among several different metals examined, gallium was unique in its ability to reduce osteocalcin mRNA levels without decreasing levels of other mRNAs synthesized by ROS 17/2.8 cells. The effects of gallium nitrate on osteocalcin mRNA and protein synthesis mimic those seen when ROS 17/2.8 cells are exposed to transforming growth factor beta 1 (TGF beta 1); however, TGF-beta 1 was not detected in gallium nitrate-treated ROS 17/2.8 cell media. Use of the RNA polymerase II inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole demonstrated that gallium nitrate did not alter the stability of osteocalcin mRNA. Transient transfection assays using the rat osteocalcin promoter linked to the bacterial reporter gene chloramphenicol acetyltransferase indicated that gallium nitrate blocked reporter gene expression stimulated by the osteocalcin promoter. This is the first reported effect of gallium nitrate on isolated osteoblast cells.

Animals↗
PubMed1994

Effects of gallium nitrate in nude mice bearing a canine adenocarcinoma (CAC-8) model of humoral hypercalcemia of malignancy.

Hypercalcemic nude mice bearing a canine adenocarcinoma (CAC-8) model of humoral hypercalcemia of malignancy (HHM) were treated daily with gallium nitrate (60 mg/kg of elemental gallium subcutaneously (SC) on day 0, followed by 20 mg/kg/day) for 5 days. Gallium nitrate significantly decreased (p < 0.01) serum calcium in tumor-bearing animals on days 2 and 5 of treatment (mean 13.7 +/- 0.7 mg/dl on day 0 versus 11.6 +/- 0.3 on day 2 and 12.4 +/- 0.5 on day 5). Urinary calcium excretion was decreased (p < 0.05) in the gallium-treated, tumor-bearing animals (0.11 +/- 0.01 mg calcium/mg creatinine) compared with hypercalcemic tumor-bearing mice (0.30 +/- 0.06). Both nontumor control and tumor-bearing mice treated with gallium nitrate lost body weight during the treatment period (p < 0.01). Gallium nitrate had no effect on tumor growth. Histomorphometric evaluation of lumbar vertebrae stained for tartrate-resistant acid phosphatase revealed a significant decrease (p < 0.05) in the number of osteoclasts/mm trabecular bone and perimeter of trabecular bone lined by active osteoblasts (p < 0.01) in the gallium-treated tumor-bearing mice compared with tumor-bearing controls. Osteoclast length (mm) was significantly increased in both the nontumor and tumor-bearing gallium-treated animals (p < 0.05) compared with nontumor and tumor-bearing control mice. Serum tumor necrosis factor alpha (TNF-alpha) levels were increased in tumor-bearing animals, but gallium nitrate had no effect on circulating levels (not detectable in nontumor control mice versus 82 +/- 21 pg/ml in tumor-bearing mice and 107 +/- 12 pg/ml in gallium-treated tumor-bearing mice).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed2000

Restaging with gallium scan identifies chemosensitive patients and predicts survival of poor-prognosis mediastinal Hodgkin's disease patients.

UNLABELLED: Following treatment of mediastinal Hodgkin's disease (HD), residual masses are frequent and gallium scanning has proven to be of value in the evaluation of their specificity (fibrosis or active disease). This study assessed, for relapse and survival, the predictive value of restaging gallium scan of patients with a residual mass on computed tomography scan after induction chemotherapy. Between 1/89 and 12/97, in 53 newly diagnosed HD patients with a residual mediastinal mass, a gallium scan was performed after chemotherapy (3 or 4 courses) and always before consolidative radiotherapy. Characteristics at diagnosis were: nodular sclerosis histology, 89%; bulky mediastinal disease, 79%; B-symptoms, 51%. RESULTS: gallium scan was positive in 16 patients (30%) and negative in 37 (70%). At median follow-up period of 36 months, freedom-from-progression rate was 86% versus 19% (P<0.0001) for patients with negative vs positive gallium scans, respectively. The 5-year overall survival (OS) rate was 68% and differed significantly (P<0.0001) between negative (91%) and positive (25%) gallium scanning groups. The specificity of gallium scanning was 91% and the sensitivity 72% with a positive predictive value of 81% and a negative predictive value of 86%. Evaluation with gallium scan after induction chemotherapy identifies chemosensitive patients among those with poor-prognosis mediastinal HD. Although relapse may occur in patients with negative gallium scan, a postive gallium scan is highly predictive of failure and poor outcome, and treatment should thus be modified.

Adult↗
PubMedDate not supplied

Uptake of aluminum and gallium into tissues of the rat: influence of antibody against the transferrin receptor.

Transport of aluminum and gallium from blood into rat tissues following continuous i.v. infusion of metals in different chemical forms has been investigated. Tissue uptake of aluminum and gallium was similar and highly dependent on the chemical species of the metals. Aluminum and gallium accumulated in liver and spleen when infused in the chloride form. Raised citrate markedly enhanced aluminum and gallium uptake into renal cortex and bone; in contrast with gallium-transferrin, citrate increased uptake of 67Ga into renal cortex and bone by 8- and 14-fold respectively. Uptake of 67Ga with citrate into renal cortex was around 3 times smaller than that of aluminum. The antitransferrin receptor antibody OX-26 enhanced 67Ga uptake from gallium citrate into all rat tissues. 67Ga from purified gallium-transferrin was also taken into all tissues in the presence of OX-26, the effect being greatest in renal cortex and bone. No influence of antibody on aluminum transport into rat tissues was, however, observed when aluminum was infused in the citrate form. Therefore, transport of aluminum and gallium into tissues is not similar under all conditions. Transport of each metal occurs into all tissues in the presence of antitransferrin receptor antibody. The potential for such transport is much greater in the case of gallium. Transport of aluminum and gallium citrate complexes appears important especially in the renal cortex and bone.

Aluminum↗
PubMedDate not supplied

Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia.

BACKGROUND: Both gallium nitrate and pamidronate are highly effective for acute control of cancer-related hypercalcemia. However, the proportion of patients who actually achieve normocalcemia has varied in published reports. Therefore, we conducted an exploratory, randomized, double-blind trial that compared the efficacy and safety of gallium nitrate and pamidronate in hospitalized patients with cancer-related hypercalcemia. PATIENTS AND METHODS: Eligible patients with hypercalcemia, defined as albumin-adjusted serum calcium > or = 12.0 mg/dL after intravenous hydration, were stratified on the basis of tumor histology (i.e., epidermoid or nonepidermoid) and by study site. Patients were then randomly assigned to receive intravenous gallium nitrate 200 mg/m2 daily for 5 days or intravenous pamidronate 60 mg (increased during the study to 90 mg for patients with initial serum calcium > or = 13.5 mg/dL) followed by placebo infusions for 4 days. The primary endpoint of the study was comparison of the proportion of patients who achieved normocalcemia. RESULTS: Sixty-four patients were randomized, and all patients were evaluable for efficacy and safety. Normocalcemia was achieved in 22 of 32 (69%) patients treated with gallium nitrate compared with 18 of 32 patients (56%) treated with pamidronate. Patients randomized to pamidronate with initial serum calcium > or = 13.5 mg/dL did not respond better to 90 mg (3 of 6; 50%) than to 60 mg (7 of 13; 54%), or compared with the response to gallium nitrate in this subset (15 of 21; 71%). Response to pamidronate was also lower in patients with epidermoid cancers (33%, vs 68% for gallium nitrate). Duration of normocalcemia was examined using both an intent-to-treat analysis irrespective of response and an analysis that examined only responding patients. By intent-to-treat analysis, the median duration of normocalcemia was 1 day for the pamidronate group and 7 days for the gallium nitrate group. Estimated normocalcemic duration in responders was 10 days for the pamidronate group and 14 days for the gallium nitrate group. Both drugs were well tolerated, and clinically significant nephrotoxicity was not observed in either treatment group. DISCUSSION: Gallium nitrate appears to be at least as effective as pamidronate for acute control of cancer-related hypercalcemia. Results from this trial suggest that gallium nitrate may be particularly useful in patients with epidermoid cancers or severe hypercalcemia at baseline, and in patients who have previously exhibited a poor response to bisphosphonates.

Bone Density Conservation Agents↗
PubMed1994

Prognostic importance of restaging gallium scans following induction chemotherapy for advanced Hodgkin's disease.

PURPOSE: This study was intended to assess the ability of restaging gallium scanning to distinguish between patients with residual radiographic abnormalities who still have active Hodgkin's disease (HD) and those who are truly complete responders. Early identification of the former patients might increase the success of secondary salvage therapy. MATERIALS AND METHODS: The charts of all patients with advanced HD treated at Duke University Medical Center during the years 1983 to 1991 who underwent gallium scanning were reviewed. Thirty-three patients were identified who had gallium scans performed as part of restaging following induction combination chemotherapy; no patient had other signs or symptoms of active or progressive HD. RESULTS: Thirteen of 33 patients had positive restaging gallium scans; 20 patients had negative scans. The 4-year actuarial relapse-free survival (RFS) rate was 75% for patients with negative restaging gallium scans compared with 8% for those with positive restaging scans (P < .001). The 4-year actuarial overall survival (OS) rate was 100% for those with negative scans compared with 51% for gallium-positive patients (P = .001). Twenty-four patients had residual chest x-ray or computed tomographic scan abnormalities. Calculated negative and positive predictive values for gallium scanning are 92% and 90%, respectively, compared with values of 48% and 83% for computed tomographic scanning. CONCLUSION: Restaging gallium scans separate complete responders from induction failures with a high degree of accuracy. Gallium scanning is clearly superior to computed tomography in this regard. Patients with advanced HD who have positive restaging gallium scans after induction chemotherapy should be classified as induction failures and are highly unlikely to be cured with involved-field low-dose radiotherapy.

Actuarial Analysis↗
PubMed1999

Photoelastic assessment of the expansion of direct-placement gallium restorative alloys.

OBJECTIVE: The purpose of this study was to assess, via a photoelastic resin, the expansion of gallium restorative alloys under conditions similar to those found in the clinical situation. METHOD AND MATERIALS: Two gallium alloys, Galloy and Gallium GF II, were tested, along with a high-copper amalgam, Dispersalloy, and a low-copper alloy, New True Dentalloy. The gallium alloys were tested as (1) uncontaminated, (2) contaminated with water, Ringer's solution, or a cell culture medium, and (3) immersed in these fluids at times ranging from 5 minutes to 3 days. The gallium and amalgam alloys were condensed in a hole drilled in a block of photoelastic resin and observed for 3 months. The amount of stress was recorded on color slides taken through polarized light at regular intervals. The photographs of the color bifringen stress patterns at 1 and 3 months were ranked by two independent evaluators for least to greatest observed stress. RESULTS: Dispersalloy had the least expansion, followed by uncontaminated Galloy and Galloy contaminated with water. Next came Galloy contaminated with cell culture medium, Galloy contaminated with Ringer's solution, contaminated New True Dentalloy, and Gallium GF II. The last group was Gallium GF II contaminated with any of the three solutions. Both gallium alloys immersed in the three fluids showed a strong edge effect, and by 6 weeks many of the gallium alloys had extruded from the mold. CONCLUSION: These results corroborate the findings of some clinical studies that have shown that these gallium alloys can potentially cause catastrophic failures.

Alloys↗
PubMedDate not supplied

Gallium maltolate is a promising chemotherapeutic agent for the treatment of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a particularly lethal cancer with few treatment options. Since gallium is known to accumulate specifically in HCC tumors but not in non-tumor liver, we investigated two gallium compounds, gallium nitrate (GaN) and gallium maltolate (GaM), as potential new agents for treating HCC. MATERIALS AND METHODS: The anti-proliferative and apoptotic activities of GaN and GaM were assessed in vitro using four HCC cell lines. HCC gene expression data was analyzed to provide a mechanistic rationale for using gallium in the treatment of HCC. RESULTS: Both compounds showed dose-dependent antiproliferative activity in all four HCC cell lines after 6-day drug exposure (IC50 values range from 60-250 microM for gallium nitrate and 25-35 microM for gallium maltolate). Gallium maltolate at 30 microM additionally induced apoptosis after 6 days. HCC gene expression data showed significantly elevated expression of the M2 subunit of ribonucleotide reductase, which is a target for the antiproliferative activity of gallium. CONCLUSION: These data support clinical testing of gallium maltolate, an orally active compound, in the treatment of HCC.

Apoptosis↗
PubMed1993

The effect of gallium nitrate on healing of vitamin D- and phosphate-deficient rickets in the immature rat.

The effect of gallium on rapid in vivo mineralization was studied in a rachitic rat model in which rickets were induced in immature rats then reversed ("healed") with repletion of vitamin D and phosphate. Gallium was administered to selected groups of animals before and during the healing phase. In nonrachitic animals and rachitic animals before healing, the mineral content of diaphyseal and metaphyseal bone was increased, and the crystal size was decreased in those animals that received gallium compared with those that did not. Mineralization of the undermineralized osteoid appeared histologically normal by 72 hours in all animals. However, animals that received gallium both before and during the healing phase had less well-mineralized bones at 18 hours, and by 72 hours, they had lesser increases in osteocalcin and mineral content, which was associated with smaller crystal sizes, than did any animal that did not receive gallium at any time. Prior to the healing phase, the ratio of gallium to hydroxyproline in the metaphyses of rachitic animals was similar to that in nonrachitic animals. Likewise, this ratio did not change in the animals receiving gallium both before and during the healing phase. The ratio of gallium to calcium was higher in rachitic animals compared with controls, and this ratio lowered significantly by the end of the healing phase. Results may be explained in part by direct effect of gallium on the physical process of mineral formation during the rapid healing phase as well as by effects of gallium on osteoblasts and osteoclasts during the induction of rickets.

Alkaline Phosphatase↗
PubMed1992

Treatment with gallium nitrate: evidence for interference with iron metabolism in vivo.

Gallium, when bound to transferrin, has been previously shown to cause tumor cell cytotoxicity by preventing cellular uptake of transferrin bound iron in vitro. Patients treated with constant infusion gallium nitrate for carcinoma show a rise in serum iron within 6 hr of the start of treatment. Serum iron returns to baseline by 24 hr post-infusion. Atomic analysis of iron and gallium content of Sephadex G-150 fractions of treatment sera indicate that about an equimolar amount of gallium and iron are associated with transferrin. These gallium and iron concentrations result in inhibition of transferrin mediated iron uptake in vitro, and in vivo allow for > 90% saturation of transferrin with metal. All seven patients who completed two courses of gallium therapy exhibited hypochromic microcytic anemia (mean fall in hemoglobin 3.5 grams %). Evidence for red cell iron depletion was confirmed by an increase (mean 3.3-fold) in zinc protoporphyrin levels. Since transferrin receptor increases on gallium treated iron requiring cells in vitro, we assessed cell surface transferrin receptor on peripheral blood lymphocytes by measuring fluorescent transferrin receptor antibody binding. A population of highly transferrin receptor positive cells peaks at 48 hr into the infusion. DNA analysis as well as double staining indicate the majority of transferrin receptor positive cells are unstimulated B lymphocytes. These studies provide the first documentation that constant infusion gallium treatment results in significant interference with iron metabolism and evidence for tissue iron depletion in vivo. These changes may correlate with therapeutic effects of gallium such as tumor response.

Animals↗
PubMed1992

Effects of gallium on bone in the rat.

Gallium nitrate lowers the serum calcium in patients with hypercalcemia caused by malignancy and is available for clinical use. The mechanism for the hypocalcemic action is unknown, however. The present studies were undertaken to determine the effects of gallium on bone metabolism. Normal male rats were implanted subcutaneously with mineralized allogeneic bone matrix. Histomorphometry of the implants and of tibiae was determined after three doses of tetracycline administered at intervals of 1 week. Gallium as nitrate was administered daily by intraperitoneal injection at doses of 0.9, 1.8, and 3.6 mg elemental gallium per kg body weight for 21 days in one study and at 3.5 mg/kg for 33 days in a second study. All the gallium-treated rats gained weight. Rats given gallium at doses of 3.5 mg/kg or more grew at a lower rate than untreated controls (-7 and -10% at doses of 3.5 and 3.6 mg/kg, respectively; p less than 0.05). At a dose of 0.9 mg/kg, gallium did not inhibit bone resorption or lower serum calcium but inhibited bone formation by 32% and bone apposition by 36% at the endosteal surface of the tibia. At a dose of 1.8 mg/kg, gallium produced modest hypocalcemia, prevented a rise in circulating 1,25-dihydroxyvitamin D [1,25-(OH)2D], inhibited bone resorption in implants, and inhibited bone formation by 19% and bone apposition by 18%. At a dose of 3.5 mg/kg, gallium lowered the serum calcium and serum 1,25-(OH)2D, inhibited growth, and accentuated the antiresorptive and antiformative effects seen at the two lower doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗