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Christopher R. Chitambar - One of the best experts on this subject based on the ideXlab platform.
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Role of Oxidative Stress in the Induction of Metallothionein-2A and Heme Oxygenase-1 Gene Expression by the Antineoplastic Agent Gallium Nitrate in Human Lymphoma Cells
Free radical biology & medicine, 2008Co-Authors: Meiying Yang, Christopher R. ChitambarAbstract:The mechanisms of action of Gallium Nitrate, an antineoplastic drug, are only partly understood. Using a DNA microarray to examine genes induced by Gallium Nitrate in CCRF-CEM cells, we found that Gallium increased metallothionein-2A (MT2A) and heme oxygenase-1 (HO-1) gene expression and altered the levels of other stress-related genes. MT2A and HO-1 were increased after 6 and 16 h of incubation with Gallium Nitrate. An increase in oxidative stress, evidenced by a decrease in cellular GSH and GSH/GSSG ratio, and an increase in dichlorodihydrofluorescein (DCF) fluorescence, was seen after 1-4 h of incubation of cells with Gallium Nitrate. DCF fluorescence was blocked by the mitochondria-targeted antioxidant mitoquinone. N-Acetyl-L-cysteine blocked Gallium-induced MT2A and HO-1 expression and increased Gallium's cytotoxicity. Studies with a zinc-specific fluoroprobe suggested that Gallium produced an expansion of an intracellular labile zinc pool, suggesting an action of Gallium on zinc homeostasis. Gallium Nitrate increased the phosphorylation of p38 mitogen-activated protein kinase and activated Nrf-2, a regulator of HO-1 gene transcription. Gallium-induced Nrf-2 activation and HO-1 expression were diminished by a p38 MAP kinase inhibitor. We conclude that Gallium Nitrate induces cellular oxidative stress as an early event which then triggers the expression of HO-1 and MT2A through different pathways.
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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
The Journal of pharmacology and experimental therapeutics, 2007Co-Authors: Christopher R. Chitambar, David P. Purpi, Jeffrey Woodliff, Meiying Yang, Janine P WereleyAbstract:Clinical studies have shown Gallium Nitrate to have significant antitumor activity against non-Hodgkin's lymphoma and bladder cancer, thus indicating that Gallium-based drugs have potential for further development as antineoplastic agents. In this study, we compared the cytotoxicity of Gallium maltolate, a novel Gallium compound, with Gallium Nitrate in lymphoma cell lines, including p53 variant and unique Gallium Nitrate-resistant cells. We found that Gallium maltolate inhibited cell proliferation and induced apoptosis through the mitochondrial pathway at lower concentrations and more rapidly than Gallium Nitrate. Gallium maltolate produced an increase in intracellular reactive oxygen species (ROS) within 2 h of incubation with cells; this effect could be blocked by mitoquinone, a mitochondria-targeted antioxidant. The role of the transferrin receptor (TfR) in Gallium maltolate's action was examined using monoclonal antibody (MoAb) 42/6 to block TfR function. However, although MoAb 42/6 reduced Gallium maltolate-induced caspase-3 activity, it had only a minor effect on cell growth inhibition. Importantly, Gallium maltolate induced apoptosis in cells resistant to Gallium Nitrate, and, unlike Gallium Nitrate, its cytotoxicity was not affected by cellular p53 status. Cellular Gallium uptake was greater with Gallium maltolate than with Gallium Nitrate. We conclude that Gallium maltolate inhibits cell proliferation and induces apoptosis more efficiently than Gallium Nitrate. Gallium maltolate is incorporated into lymphoma cells to a greater extent than Gallium Nitrate via both TfR-independent and -dependent pathways; it has significant activity against Gallium Nitrate-resistant cells and acts independently of p53. Further studies to evaluate its antineoplastic activity in vivo are warranted.
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Gene expression analysis of Gallium-resistant and Gallium-sensitive lymphoma cells reveals a role for metal-responsive transcription factor-1, metallothionein-2A, and zinc transporter-1 in modulating the antineoplastic activity of Gallium Nitrate.
Molecular cancer therapeutics, 2007Co-Authors: Meiying Yang, Steven H. Kroft, Christopher R. ChitambarAbstract:Several clinical trials have shown Gallium Nitrate to be an active agent in the treatment of lymphoma. Whereas Gallium is known to target cellular iron homeostasis, the basis for lymphoma cell resistance to Gallium is not known. Understanding mechanisms of resistance may suggest strategies to enhance the clinical efficacy of Gallium. In the present study, we used a focused DNA microarray to compare the expression of genes related to metal metabolism in Gallium-resistant and Gallium-sensitive lymphoma cell lines developed by us. Gallium-resistant cells were found to display a marked increase in gene expression for metallothionein-2A and the zinc transporter ZnT-1. Cells exposed to Gallium Nitrate displayed an increase in the binding of metal-responsive transcription factor-1 to metal response element sequences involved in the transcriptional regulation of metallothionein and ZnT-1 genes. Gallium Nitrate induced metallothionein-2A and ZnT-1 expression in cells. A role for metallothionein in modulating the antineoplastic activity of Gallium was confirmed by showing that the induction of metallothionein expression by zinc provided partial protection against the cytotoxicity of Gallium and by showing that the level of endogenous metallothionein in lymphoma cell lines correlated with their sensitivity to Gallium Nitrate. Immunohistochemical staining of lymphomatous tissues revealed metallothionein protein to be variably expressed in different lymphomas. Our studies show for the first time that Gallium acts on pathways related to zinc metabolism and that metal-responsive transcription factor-1 activity and metallothionein expression contribute to the development of Gallium drug resistance. Furthermore, the endogenous level of metallothionein in lymphoma may be an important determinant of clinical response to Gallium Nitrate.
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Apoptotic mechanisms of Gallium Nitrate: basic and clinical investigations.
Oncology (Williston Park N.Y.), 2004Co-Authors: Christopher R. ChitambarAbstract:Gallium Nitrate inhibits the growth of various lymphoma cell lines in vitro and exhibits antitumor activity in patients with lymphoma. The mechanism(s) of cytotoxicity is (are) only partly understood but appears to involve a two-step process: (1) targeting of Gallium to cells, and (2) acting on multiple, specific intracellular processes. Gallium shares certain chemical properties with iron; therefore, it binds avidly to the iron transport protein transferrin. Transferrin-Gallium complexes preferentially target cells that express transferrin receptors on their surface. Expression of transferrin receptors is particularly high on lymphoma cells. Cellular uptake of the Gallium-transferrin complex leads to inhibition of cellular proliferation primarily via disruption of iron transport and homeostasis and blockade of ribonucleotide reductase. Recent studies have shown that cellular uptake of Gallium leads to activation of caspases and induction of apoptosis. In phase II trials in patients with relapsed or refractory lymphoma, the antitumor activity of Gallium Nitrate is similar to, or better than, that of other commonly used chemotherapeutic agents. Gallium Nitrate is not myelosuppressive and may be used in patients with neutropenia or thrombocytopenia. A multicenter trial to evaluate the use of Gallium Nitrate in patients with relapsed non-Hodgkin's lymphoma is currently ongoing.
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Gallium Nitrate for the treatment of non-Hodgkin's lymphoma.
Expert opinion on investigational drugs, 2004Co-Authors: Christopher R. ChitambarAbstract: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 ...
Richard S. Bockman - One of the best experts on this subject based on the ideXlab platform.
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Gallium Nitrate for Acute Treatment of Cancer-Related Hypercalcemia
Annals of Internal Medicine, 2020Co-Authors: Raymond P. Warrell, Robert Israel, Marianne Frisone, Teresa Snyder, Jeffrey J. Gaynor, Richard S. BockmanAbstract:Abstract Study Objective:To determine whether Gallium Nitrate therapy is superior to maximally approved doses of calcitonin for acute control of cancer-related hypercalcemia. Design:Randomized, dou...
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Gallium Nitrate for Advanced Paget Disease of Bone: Effectiveness and Dose-Response Analysis
2016Co-Authors: Raymond P. Warrell, Joseph Lane, Richard S. BockmanAbstract:Objective: To evaluate whether a brief course of treatment with Gallium Nitrate can reduce biochemical parameters of accelerated bone turnover in patients with advanced Paget disease. Design: Unblinded trial, decreasing dose schedules of Gallium Nitrate. Setting: University hospital with primary orthopedic and meta-bolic bone disease specialty. Patients: Ten patients with advanced Paget disease who had previously received conventional therapy consisting of calcitonin, etidronate, or mithramycin. Interventions: Five patients were entered into each of three dose schedules: 2.5 mg/kg body weight per day by continuous intrave-nous infusion for 7 days; 0.5 mg/kg per day for 14 days by subcutaneous injection; and 0.25 mg/kg per day for 14 days by subcutaneous injection. Several patients were treated with differen
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Rapid Publication Gallium Nitrate Inhibits Calcium Resorption from Bone and Is Effective Treatment
2016Co-Authors: For Cancer-related Hypercalcemia, Richard S. Bockman, Raymond P. Warrell, Craig J. Coonley, Marian Isaacs, Harry StaszewskiAbstract:Abstract. Approximately two-thirds ofpatients who receive the anticancer drug Gallium Nitrate develop mild hypocalcemia. To evaluate the mechanism of drug-induced hypocalcemia, we tested the effects of Gallium Nitrate upon in vitro release of "5Ca"+ from explanted fetal rat bones. The drug significantly inhibited 45Ca`+ release in response to stimulation with both parathyroid hormone and a lymphokine preparation with osteoclast activating factor activity. The inhibitory effects on bone resorption were both time- and dose-dependent. Later, in a pilot study, we treated 10 patients who had cancer-related hypercalcemia with Gallium Nitrate administered by continuous infusion. All patients responded by a re-duction of total serum calcium to normal or subnormal concentrations (13.8±1.05 mg/dl, mean±SD pretreat-ment, to 8.03±1.03 mg/dl, mean posttreatment nadir). Our results indicate that Gallium Nitrate effectively treats cancer-related hypercalcemia and that it probably acts by inhibiting calcium release from bone
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Gallium Nitrate regulates rat osteoblast expression of osteocalcin protein and mRNA levels.
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2009Co-Authors: P.t. Guidon, Roberto Salvatori, Richard S. BockmanAbstract: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.
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A multicenter trial of low dose Gallium Nitrate in patients with advanced Paget's disease of bone
The Journal of clinical endocrinology and metabolism, 1995Co-Authors: Richard S. Bockman, Barbara J. Bosco, Francois Wilhelm, Ethel S. Siris, Frederick Singer, Arthur Chausmer, Rachelle Bitton, Jon Kotler, David R. Eyre, David LevensonAbstract:Gallium Nitrate is a potent antiresorptive drug that has been extensively tested in patients with accelerated bone turnover. We have evaluated the effects of this new agent in a pilot multicenter trial of 49 patients with advanced Paget's disease of bone. Patients were randomized to receive 0.05, 0.25, or 0.5 mg/kg.day Gallium Nitrate administered by sc injection in two 14-day cycles. Serum alkaline phosphatase, fasting 2-h urinary hydroxyproline and N- telopeptide collagen cross-links excretion, and quality of life were assessed every 2 weeks for 12 weeks. The group mean alkaline phosphatase activity at baseline was 854 +/- 100 (+/- SEM) IU/L. The mean changes from baseline to week 12 in serum alkaline phosphatase were +0.5%, -24%, and -31%, respectively, for the three doses tested. The differences for each of the higher dose levels (0.25 and 0.5 mg/kg.day) was statistically significant (P < or = 0.05), and nearly half of the patients treated with the 0.5 mg/kg.day dose achieved a 50% or more reduction in enzyme activity. The nadir value in hydroxyproline excretion occurred at 10 weeks, with mean changes of +9%, -10%, and -17% for the 0.05, 0.25, and 0.5 mg/kg.day doses, respectively; the difference was significant only at the 0.5 mg/kg.day level (P < 0.01). Urinary collagen cross-link excretion showed a significant decrease at the 0.25 and 0.5 mg/kg.day doses. We also observed a definite, but nonsignificant, trend for improved quality of life in patients treated at the highest drug dose. Minor discomfort at the injection site was frequently reported, but did not lead to interruption of therapy. Our results in these patients who had received moderate to extensive prior therapies with other drugs show that cyclical, low dose, sc administration of Gallium Nitrate is safe and effective for treating patients with advanced Paget's disease of bone.
Brian Leyland-jones - One of the best experts on this subject based on the ideXlab platform.
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Treating cancer-related hypercalcemia with Gallium Nitrate.
The journal of supportive oncology, 2004Co-Authors: Brian Leyland-jonesAbstract:Gallium Nitrate is an approved therapy for symptomatic, cancer-related hypercalcemia unresponsive to adequate hydration, the most common life-threatening metabolic disorder of cancer. Initially developed because of its antineoplastic properties, Gallium Nitrate demonstrated the ability to reduce serum calcium levels in early trials. Although the mechanism by which Gallium Nitrate corrects hypercalcemia is not fully understood, it appears to involve multiple effects (inhibition of osteoclast-mediated bone resorption, stimulation of bone formation, and alteration of the mineral composition and properties of bone); however, Gallium Nitrate is not cytotoxic to bone cells. In randomized trials for moderate-to-severe cancer-related hypercalcemia, Gallium Nitrate was well tolerated and produced a higher rate and longer duration of normocalcemia relative to calcitonin and the bisphosphonates etidronate and pamidronate. Gallium Nitrate induced normocalcemia in 72% to 82% of patients; in contrast to the comparator agents, it was effective regardless of epidermoid tumor status. Epidermoid tumors are associated with high levels of parathyroid hormone-related protein (PTHrP), the principal mediator of cancer-related hypercalcemia in solid tumors. High levels of PTHrP appear to adversely impact the calcium-lowering potential of bisphosphonates. The recommended schedule of Gallium Nitrate for the treatment of cancer-related hypercalcemia is 200 mg/m2 per day as a 5-day continuous intravenous infusion, administered with adequate hydration and close monitoring of renal function. Gallium Nitrate is an effective treatment option for moderate-to-severe cancer-related hypercalcemia, a setting in which morbidity and mortality are high.
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Treatment of cancer-related hypercalcemia: the role of Gallium Nitrate.
Seminars in oncology, 2003Co-Authors: Brian Leyland-jonesAbstract:Hypercalcemia is a common, life-threatening metabolic disorder that can be associated with cancer. Its pathophysiology includes enhanced osteoclastic bone resorption and decreased renal excretion of extracellular calcium. Symptoms of hypercalcemia include nausea, vomiting, bone pain, polyuria, renal insufficiency, bradycardia, and arrhythmia. The goals of medical therapy are to inhibit bone resorption and promote renal calcium excretion. Hydration is the first step in management. Treatments for hypercalcemia include phosphates, calcitonin, bisphosphonates, and Gallium Nitrate. Although intravenous phosphates prevent intestinal calcium absorption and inhibit mineral and bone matrix resorption, serious adverse events include renal failure, hypotension, extraskeletal calcification, and severe hypocalcemia. Calcitonin has a rapid onset of action and can lower serum calcium concentrations within hours, but its usefulness is limited by its short duration of effect and the development of tachyphylaxis. Bisphosphonates are effective inhibitors of bone resorption but appear to have decreased response rates in hypercalcemic patients with high levels of parathyroid-related protein. Gallium Nitrate, an antitumor agent noncytotoxic to osteoclasts and bone cells, appears to be more effective than pamidronate, etidronate, and calcitonin in the treatment of cancer-related hypercalcemia. Importantly, unlike bisphosphonates, Gallium Nitrate is effective in both parathyroid-related protein-mediated and non-parathyroid-related protein-mediated hypercalcemia.
L. Z. Zanoni Consolo - One of the best experts on this subject based on the ideXlab platform.
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Thermal decomposition of Gallium Nitrate hydrate and modeling of thermolysis products
Journal of Thermal Analysis and Calorimetry, 2011Co-Authors: Petr Melnikov, Valter Aragão Do Nascimento, L. Z. Zanoni ConsoloAbstract:It is well established that Gallium insertion into the hydroxiapatite matrix as practiced in orthopedics protects bone from resorbtion and improves the biomechanical properties of the skeletal system. The research presented in this article is an investigation into the thermal decomposition of Gallium Nitrate, which is part of a complex process leading to the preparation of a hybrid matrix. It was demonstrated that after melting of the hexahydrate in its own water there occurs a simultaneous condensation of 4 mol of initial monomer Ga(NO3)3·6H2O into a tetramer Ga4O4(NO3)4. The resulting inorganic cycle gradually loses N2O5 and, through the formation of unstable oxyNitrates, is transformed into Gallium oxide. The use of molecular mechanics for comparing the potential energies of consecutive products of thermal decomposition permitted an evaluation of their stability and an appropriate interpretation of the experimental data.
Graziela Garrido Mori - One of the best experts on this subject based on the ideXlab platform.
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RESUMO MORPHOMETRIC AND MICROSCOPIC EVALUATION OF THE EFFECT OF Gallium Nitrate AS A ROOT CANAL DRESSING IN RAT TEETH SUBMITTED TO LATE REPLANTATION
2016Co-Authors: Avaliação Morfométrica, E Microscópica, Do Efeito, Do Nitrato, De Gálio, Usado Como, Curativo Intracanal, Em Dentes, De Ratos Reimplantados, Graziela Garrido MoriAbstract:he purpose of this study was to test a Gallium Nitrate solution, a resorption inhibitor, employed as a root canal dressing in teeth submitted to late replantation. Thirty maxillary right central incisors of rats were avulsed and kept dry for thirty minutes. The teeth were instrumented and the root surfaces were treated with 1 % hypochlorite solution followed by application of 2% sodium fluoride. Thereafter, the teeth were divided into two groups according to the root canal dressing: Group I, solution of Gallium Nitrate; and Group II, calcium hydroxide paste. The teeth were then replanted in their respective sockets. The animals were killed at 15, 30 and 60 days after replantation and the samples were processed for morphometric and microscopic analysis. The results demonstrated that the Gallium Nitrate solution and the calcium hydroxide paste limited the root resorption, yet they did not impair its occurrence. It may be concluded that Gallium Nitrate solution and calcium hydroxide paste demonstrated similar performance. Uniterms: Gallium; Root resorption; Tooth replantation; Tooth avulsion. ste trabalho tem como objetivo testar a solução de nitrato de gálio, um inibidor da reabsorção, como curativo intracanal para dentes reimplantados tardiamente. Trinta incisivos centrais superiores direitos de ratos foram avulsionados e mantidos
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Microscopic Investigation of the Use of Gallium Nitrate for Root Surface Treatment in Rat Teeth Submitted to Delayed Replantation
Brazilian dental journal, 2007Co-Authors: Graziela Garrido Mori, Roberto Brandão Garcia, Ivaldo Gomes De Moraes, Lilian Cristina Baraldi Borro, Bruno Rombaldi PurificaçãoAbstract:The aim of this study was to investigate the effect of Gallium Nitrate solution, an anti-resorption substance, when applied for root surface treatment in rat teeth submitted to delayed replantation, in order to inhibit the root resorption process and enhance repair. For such purpose, 20 maxillary right central incisors of rats were randomly assigned to 2 groups (n=10). In group I, root surface was treated with 10-4M Gallium Nitrate solution for 20 min, while in group II root surface was treated with 2% sodium fluoride for 20 min. All root canals were filled with a calcium hydroxide-based paste. At 15 and 60 days after replantation, the animals were killed and the specimens were processed in laboratory for light transmission microscopy. In both groups, there was mild occurrence of ankylosis and root resorption. The connective tissue formed at the periodontal ligament area was arranged parallel to the root in most specimens in both groups and presented signs of inflammation. In group I, there was periodontal pocket formation in all specimens at 60 days, revealing lack of repair. These findings contraindicate the use of Gallium Nitrate for root surface treatment of teeth submitted to late replantation.
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Morphometric and microscopic evaluation of the effect of Gallium Nitrate as a root canal dressing in rat teeth submitted to late replantation
Journal of applied oral science : revista FOB, 2006Co-Authors: Graziela Garrido Mori, Roberto Brandão Garcia, Ivaldo Gomes De Moraes, Clóvis Monteiro Bramante, Norberti BernardineliAbstract:The purpose of this study was to test a Gallium Nitrate solution, a resorption inhibitor, employed as a root canal dressing in teeth submitted to late replantation. Thirty maxillary right central incisors of rats were avulsed and kept dry for thirty minutes. The teeth were instrumented and the root surfaces were treated with 1% hypochlorite solution followed by application of 2% sodium fluoride. Thereafter, the teeth were divided into two groups according to the root canal dressing: Group I, solution of Gallium Nitrate; and Group II, calcium hydroxide paste. The teeth were then replanted in their respective sockets. The animals were killed at 15, 30 and 60 days after replantation and the samples were processed for morphometric and microscopic analysis. The results demonstrated that the Gallium Nitrate solution and the calcium hydroxide paste limited the root resorption, yet they did not impair its occurrence. It may be concluded that Gallium Nitrate solution and calcium hydroxide paste demonstrated similar performance.
