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PubMedDate not supplied

Gallium-pyridoxal isonicotinoyl hydrazone (Ga-PIH), a novel cytotoxic gallium complex. A comparative study with gallium nitrate.

The anti-proliferative activity of gallium-pyridoxal isonicotinoyl hydrazone (Ga-PIH), a novel gallium complex was compared with that of gallium nitrate, a known anti-tumor agent. At 50 microM, Ga-PIH inhibited CCRF-CEM cell growth by 45% compared to < 10% inhibition with gallium nitrate or PIH. The IC50s for Ga-PIH, gallium nitrate and PIH were 60, 84 and 68 microM respectively. The addition of exogenous iron as transferrin-iron to the culture medium reversed the cytotoxicity of gallium nitrate and PIH in a dose-dependent manner but had only minor effects on the cytotoxicity of Ga-PIH. The effect of these compounds on cellular iron uptake was measured since prior studies have shown that gallium perturbs iron transport into cells. Fifty micromolar Ga-PIH, gallium nitrate or PIH inhibited the cellular uptake of 59Fe-transferrin over 24 h by 65%, 32%, and 78% respectively. Although all three compounds inhibited iron uptake, only Ga-PIH produced a significant upregulation of cellular transferrin receptors. Since the cytotoxicity of Ga-PIH appears to be less influenced by extracellular iron and cellular transferrin receptor expression, it may have potential as an antineoplastic agent and should be further evaluated in animal tumor models.

Antineoplastic Agents↗
PubMedDate not supplied

Preclinical toxicology and tissue gallium distribution of a novel antitumour gallium compound: tris (8-quinolinolato) gallium (III).

Tris (8-chinolinolato) gallium (III) compound (KP46), a new organo-metallic gallium (Ga) complex, has been synthesized for potential use in anticancer therapy. Although this agent has a better bioavailability after oral administration than Ga chloride, it also shows a greater toxicity. The purpose of the present study was to assess the acute and subacute toxicity of KP46, and to determine tissue Ga distribution in healthy Swiss mice. Ga assays were performed by inductively coupled plasma atomic emission spectrometry. In the first experiment, the drug was given by gavage at single doses ranging from 464 to 4640 mg/kg. The LD50 values were 2870 mg/kg (410 mg Ga3+/kg) and 2370 mg/kg (339 mg Ga3+/kg) for males and females, respectively. In the second experiment, KP46 was administered by gavage at 0, 62.5, 125, 250, 500 and 750 mg/kg/day for two weeks (8 animals/dose/sex). The dose of 62.5 mg/kg/day was well tolerated, without deaths, decreased weight gain, or renal, hepatic and hematological toxicities. Higher doses decrease the probability of survival. A significant decrease in the number of white blood cells was noted at doses of 125 mg/kg/day (p<0.05), while hemoglobin, hepatic and renal functions were not affected. At 62.5 mg/kg/day, the Ga concentrations were 7.02 +/- 3.14 microg/g in bone, 3.55 +/- 2.10 microg/g in the liver, 1.81 +/- 0.24 microg/g in the kidneys, 1.77 +/- 1.45 microg/g in the spleen. In lungs, brain, testes and ovaries, the Ga concentrations were under the limit of detection (0.030 ng/g). According to these results, the therapeutic potential of KP46, orally administered, should be evaluated with the dose of 62.5 mg/kg/day. The great affinity of Ga for bone could justify the consideration of KP46 for malignant bone tumours.

Administration, Oral↗
PubMed1996

Evaluation of transferrin and gallium-pyridoxal isonicotinoyl hydrazone as potential therapeutic agents to overcome lymphoid leukemic cell resistance to gallium nitrate.

Gallium nitrate is active against lymphoma and bladder cancer; however, little is understood about tumor resistance to this drug. Transferrin, the iron transport protein, increases gallium uptake by cells, whereas pyridoxal isonicotinoyl hydrazone (PIH), an iron chelator, transports iron into cells. Therefore, we examined whether these metal transporters would increase the cytotoxicity of gallium in gallium nitrate-resistant CCRF-CEM cells. Transferrin, in increasing concentrations, enhanced the cytotoxicity of gallium nitrate. One mg/ml transferrin decreased the 50% inhibitory concentration of gallium nitrate from 1650 to 75 micrometer in gallium-resistant cells and from 190 to 150 micrometer in gallium-sensitive cells. Transferrin also enhanced the cytotoxicity of gallium even at drug concentrations that were not growth inhibitory. The gallium chelate Ga-PIH inhibited the growth of both gallium nitrate-resistant and -sensitive cells. Fifty micrometer Ga-PIH inhibited cellular proliferation by 50%, whereas similar concentrations of PIH or gallium nitrate were not growth inhibitory. However, because higher concentrations of PIH also inhibited cell growth, the cytotoxicity of Ga-PIH was greater than PIH only at concentrations of <100 micrometer. Cross-titration experiments demonstrated that the cytotoxicity of PIH was partially reversed by gallium nitrate, whereas the cytotoxicity of gallium nitrate was enhanced by PIH. Our studies suggest that Ga-PIH warrants further evaluation as a potential antineoplastic agent. Because transferrin increases the cytotoxicity of gallium nitrate in transferrin receptor-bearing, gallium nitrate-resistant cells, future clinical trials of this drug should incorporate the development of strategies to increase plasma transferrin levels.

Antineoplastic Agents↗
PubMed2005

Elimination of arthritis pain and inflammation for over 2 years with a single 90 min, topical 14% gallium nitrate treatment: case reports and review of actions of gallium III.

Arthritis is inflammation in a joint often with joint damage, usually accompanied by pain, swelling and stiffness, resulting from infection, trauma, degenerative changes, metabolic disturbances, autoimmune or other causes. It occurs in various forms, including rheumatoid arthritis, osteoarthritis, bacterial arthritis and gout. Gallium III can inhibit the production of inflammatory cytokines, such as IL-1beta, produced by macrophage-like cells in vitro. A dose-dependent inhibition of IL-1beta and TPA stimulated MMP activity by gallium nitrate at increasing concentrations occurs, demonstrating that gallium nitrate can be a useful modulator of inflammation in arthritis. Gallium III is an inhibitor of bone resorption and is an effective treatment for hypercalcemia. Gallium III has been reported to be effective in the treatment of mycobacterium butycicum-induced arthritis in rats by antagonism of iron III. Long-term elimination of pain from arthritis by gallium III was first observed in horses primarily being treated for navicular disease. Several people treating their horses with gallium nitrate coincidentally found that arthritis pain in their fingers ended and did not return after soaking their hands in 14% gallium nitrate solution. Therefore, the severely arthritic hands of a 60-year-old woman were topically treated with a 14% aqueous solution of gallium nitrate for 90 min. Pain and inflammation from rheumatoid arthritis diminished rapidly, and neither pain nor inflammation returned during the following 2 years from that single treatment. A 61-year-old woman who had osteoarthritis in her left knee, shoulders and wrists was treated orally with 50 ml of a 1% gallium nitrate solution (120 mg elemental gallium) daily using a two week on and two week off protocol, resulting in almost total elimination of pain while on gallium nitrate, while pain partially returned during the two week off periods. Treatment of frozen shoulder with topical 40% gallium nitrate for 120 min resulted in greatly reduced pain and crepitus almost immediately with complete restoration of range of motion, with pain remaining essentially absent for over 1 year. Mechanisms of action are hypothesized to include anti-inflammatory, bone density improvements, antibacterial, anti-iron III and anti-aluminum III effects. Proper use of gallium III may be effective in terminating pain and inflammation of arthritis for years, often with a single treatment.

Arthralgia↗
PubMed1988

Tissue distribution of gallium following administration of the gallium-maltol complex in the rat: a model for an aluminium-maltol complex of neurotoxicological interest.

The intestinal absorption and subsequent tissue distribution of aluminium-maltol, a potentially neurotoxic complex found in foods, was investigated using gallium as a marker for aluminium. Gallium or gallium-maltol labelled with 67Ga was administered orally to rats. The amount of gallium in 'blood-free' tissues was measured by correcting for gallium in residual blood and an estimate of intestinal absorption was then made by summing the values for all tissues examined. In both the test (gallium-maltol dosed) and control (gallium only dosed) experiments absorption of gallium was significantly increased in the fasted state when compared with that of the fed animals. In fasted but not in fed animals, administration of gallium-maltol doubled the amount of gallium absorbed when compared with administration of gallium alone.

Aluminum↗
PubMed1995

The effect of free gallium and gallium in liposomes on cytokine and nitric oxide secretion from macrophage-like cells in vitro.

The aim of this study was to evaluate the effect of gallium nitrate, gallium-nitrilotriacetate (NTA) complex, and liposomal gallium-NTA on IL-6, TNF alpha, and nitric oxide (NO) release from activated macrophages. In addition, the expression of the inducible nitric oxide synthase (iNOS) was determined. Gallium inhibited dose-dependently the secretion of IL-6, TNF alpha, and NO from the LPS-induced macrophage-like RAW 264 cells. Encapsulation of gallium in negatively charged DSPG-liposomes increased its potency 10-50 times and 7-11 times compared to free gallium nitrate and gallium-NTA, respectively. Neither non-loaded liposomes nor NTA alone inhibited cytokine or NO secretion, demonstrating that the observed effects originated from gallium. Liposomal gallium-NTA inhibited the expression of iNOS by the macrophages, while other formulations of gallium had no effect. Thus, gallium, when delivered properly, suppresses macrophage functions by inhibiting the release of inflammatory mediators from the cells.

Animals↗
PubMed1996

Modulation of in vitro and in vivo T-cell responses by transferrin-gallium and gallium nitrate.

Gallium is a group IIIa metal that has efficacy in the therapy of malignant disorders such as lymphoma and urothelial tract tumors. Preclinical studies also indicate a role for gallium in autoimmune disorders, suggesting that gallium is able to modulate T-cell immune reactivity. The purpose of this study was to examine the in vitro and in vivo immunomodulatory action of gallium on T-cell function. Since gallium binds to transferrin in vivo, in vitro studies evaluated the effect of transferrin-gallium (Tf-Ga) on human T cells. Tf-Ga inhibited the mitogen-induced proliferative response of peripheral blood mononuclear cells (PBMC) in a dose-dependent fashion. Alloantigen-induced proliferation was also potently suppressed when evaluated in a mixed lymphocyte culture assay. Tf-Ga affected a significant reduction in the density of IL-2 receptors on activated T cells and a slight reduction in the number of CD3+/CD25+ T cells in PHA-stimulated cultures. Neither secretion of interleukin-2 (IL-2) nor the induction of IL-2-stimulated lymphokine-activated killer activity, however, was inhibited by Tf-Ga. Tf-Ga produced significant upregulation of the transferrin receptor (CD71) in T cells as determined by flow cytometric analysis and northern blot assay, but did not affect the percentage of CD3+/ CD71+ T cells after mitogen stimulation. To assess the in vivo effects of gallium on alloreactive T cells, we evaluated the immunosuppressive effect of gallium in a murine model of graft-versus-host disease (GVHD). Administration of gallium significantly prolonged survival in mice undergoing severe GVHD, suggesting that gallium can ameliorate GVH reactivity. Collectively, these data demonstrate that, at clinically achievable concentrations, Tf-Ga potently inhibits T-cell activation and that this immunosuppressive property of gallium may be of adjunctive therapeutic value in the management of disorders characterized by the presence of autoreactive or alloreactive T-cell populations.

Animals↗
PubMed2005

Resistance to the antineoplastic agent gallium nitrate results in marked alterations in intracellular iron and gallium trafficking: identification of novel intermediates.

Gallium (Ga) shows significant antitumor activity by markedly interfering with iron (Fe) metabolism, and (67)Ga is used as a radio-imaging agent for cancer detection. Therefore, the mechanisms involved in (67)Ga uptake, metabolism, and resistance are critical to understand. The development of tumor lines that are gallium-resistant suggests (67)Ga uptake may be different in these cells, providing an opportunity for understanding intracellular (67)Ga and (59)Fe transport and gallium resistance. In this study, gallium-resistant cells were used to assess (67)Ga and (59)Fe uptake using native polyacrylamide gel electrophoresis autoradiography. In contrast to the common view that (67)Ga and (59)Fe use the same uptake pathways, we show that the trafficking of these two metal ions is different in cells either resistant (R) or sensitive (S) to gallium. Indeed, in contrast to (59)Fe, little (67)Ga is incorporated into ferritin, with most present as a labile (67)Ga pool. We also report unique changes in (67)Ga and (59)Fe trafficking between R and S cells. In particular, in R cells, there was a distinct transferrin-transferrin receptor 1-hemochromatosis protein (HFE) complex (band B) not observed in S cells. Furthermore, because HFE regulates iron and gallium uptake, the two Tf-TfR1-HFE complexes in R cells may be involved in reduced (67)Ga and (59)Fe uptake compared with S cells. In S cells, a novel iron-binding intermediate (band D) was identified that was not present in R cells and may be a "sensitivity factor" to gallium. In contrast to the general view that (67)Ga and (59)Fe use the same or similar uptake pathways, we show that their distribution and trafficking is markedly different in R and S cells.

Antineoplastic Agents↗
PubMed1986

Comparative pulmonary toxicity of gallium arsenide, gallium(III) oxide, or arsenic(III) oxide intratracheally instilled into rats.

The relative toxicity of gallium arsenide (GaAs) and its metal oxides was assessed by intratracheally instilling particulate suspensions of GaAs (100 mg/kg), equimolar gallium as Ga2O3 (65 mg/kg), or a maximally tolerated nonlethal dose of arsenic as As2O3 (17 mg/kg). Two weeks after dosing, five rats from each group were randomly selected for the biochemical determination of lung lipid, protein, DNA, and collagen (4-hydroxyproline; 4-HP) content. The pulmonary retention of gallium and/or arsenic and the concentration of these metals in blood were also determined. Lungs from the remaining rats (n = 3) were examined histopathologically. Pulmonary exposure to Ga2O3 particulates significantly (p less than 0.05) increased the total lipid content of lungs relative to that observed in the vehicle-treated control animals. This response appeared to be associated with the pulmonary retention of gallium particulates (means = 36% of the gallium dose). In contrast, As2O3 particulates were not retained in the lung. Blood arsenic concentrations were 36 ppm which represented 20% of the total arsenic administered. Treatment with As2O3 significantly elevated lung dry weight as well as protein, DNA, and 4-HP content. These data suggest that As2O3 induced an acute fibrogenic response. The intratracheal instillation of GaAs particulates produced effects similar to those observed with the individual oxides. The total lung content of lipids, protein, and DNA was significantly elevated. These biochemical changes were accompanied by significant increases in lung dry weight and lung wet weight. Lungs from rats receiving GaAs particulates retained 44% of the dose as gallium and 28% of the dose as arsenic at the end of the 14-day study. Blood arsenic concentrations were 44 ppm (7% of the arsenic dose) while gallium was not detected in blood at this time. The primary histopathological observations 14 days after the intratracheal instillation of all metal particulates were an inflammatory response and pneumonocyte hyperplasia. The biological severity of these lesions, in descending order, was GaAs greater than As2O3 much greater than Ga2O3. It must be noted, however, that As2O3 was dosed at 0.25 X moles of GaAs.

Analysis of Variance↗
PubMed1978

The interactions of gallium with various buffers and chelating agents in aqueous solution: gallium-71 and hydrogen-1 NMR studies.

The interactions of gallium (Ga) with the ligands, EDTA, NTA, phosphate, lactate, MOPS, TRIS and HEPES are investigated using both 71Ga and 1H nmr measurements. Both EDTA and NTA form strong complexes with gallium, which have a 1:1 stoichiometry. In alkaline solution the tetrahedral Ga(OD)4- competes strongly with EDTA in complex formation. In the lactate complex, there are probably three lactates per gallium present. The phosphate complexes of gallium are difficult to characterize on the basis of this investigation. The buffers, MOPS, TRIS, and HEPES, do not interact with gallium significantly. The ability of the ligands to bind gallium correlates well with their ability to inhibit gallium incorporation by L1210 leukemic cells.

Buffers↗
PubMed1998

Mechanisms of uptake of gallium by human neuroblastoma cells and effects of gallium and aluminum on cell growth, lysosomal protease, and choline acetyl transferase activity.

We have studied the uptake and removal of gallium, used as an analogue of aluminum, and the effects of aluminum itself on cultured human neuroblastoma cells treated with soluble metal complexes. The prohibitively high cost of measurement of the only available radioisotope of aluminum (26Al) precluded its usage, and so we considered that gallium, which is chemically extremely similar, would be the most suitable model. Gallium has been used thus in a number of previous biological studies and has been found to behave like aluminum in many respects. We have previously shown that Al-EDTA treatment results in uptake of aluminum and expression of hyperphosphorylated tau, a key component of Alzheimer's disease paired helical filaments. Here we demonstrate that gallium uptake can occur by two separate methods, both leading to physiologically relevant intracellular metal concentrations. Uptake from medium containing bovine transferrin occurred mainly by pinocytosis, but in the presence of human transferrin (hTf), uptake by transferrin-mediated endocytosis occurred also, despite a very low level of hTf saturation, indicating that Tf-mediated uptake is a very effective method of Ga internalization. The intracellular gallium is relatively stable, though partially removable by (1 mM) EDTA, desferrioxamine, or 1,2-dimethyl-3-hydroxypyrid-4-one. Aluminum and gallium treatment were found to increase the overall activity of lysosomal proteases, enzymes implicated in amyloid precursor protein cleavage. No effects were detected on choline acetyl transferase activity, cell growth, or tritiated thymidine incorporation or on the structure of the cells, as judged by light or electron microscopy.

Aluminum↗
PubMed1989

[A basic study on gallium alloys for dental restorations. Improvement of liquid gallium alloy].

This study was made to compare the physical and chemical properties of amalgam with those of gallium alloy in which the invented liquid alloy containing the three fundamental components of Ga-Sn-In or Ga-Sn-In-Ag were used instead of mercury. Experiment 1. The physical and chemical properties were investigated after the liquid gallium alloy and high copper amalgam powder were mixed. The following results were obtained; 1) The invented gallium alloy group showed expansion in dimensional changes immediately after mixing. This alloy group showed the same compressive and diametral tensile strength as those in amalgam after 7 days. 2) This alloy group showed slightly more corrosion weight loss in 0.05% HCl and 1% lactic acid solutions than that in amalgam, but this alloy group showed the same corrosion weight loss in 1% NaCl solution and artificial saliva as in amalgam. Also this alloy group showed more discoloration (delta E, NBS) in 0.1% Na2S solution than that in amalgam, but this showed the same degree of discoloration in artificial saliva. Experiment 2. The physical and chemical properties were investigated after the same liquid gallium alloy and Ag-Pd-Sn-Cu-Zn alloy powder were mixed. The following results were obtained; 1) The invented gallium alloy group showed expansion in dimensional changes immediately after mixing. This showed superior quality in compressive and diametral tensile strength as compared with those of amalgam. 2) The invented gallium alloy showed slightly more corrosion weight loss in 0.05% HCl and 1% lactic acid solutions than that in amalgam, but this alloy group showed the same corrosion weight loss in 1% NaCl solution and artificial saliva as in amalgam. Also this alloy group showed more discoloration (delta E, NBS) in 0.1% solution than that in amalgam, but it was the same in artificial saliva.

Dental Alloys↗
PubMed2004

Toxicity of indium arsenide, gallium arsenide, and aluminium gallium arsenide.

Gallium arsenide (GaAs), indium arsenide (InAs), and aluminium gallium arsenide (AlGaAs) are semiconductor applications. Although the increased use of these materials has raised concerns about occupational exposure to them, there is little information regarding the adverse health effects to workers arising from exposure to these particles. However, available data indicate these semiconductor materials can be toxic in animals. Although acute and chronic toxicity of the lung, reproductive organs, and kidney are associated with exposure to these semiconductor materials, in particular, chronic toxicity should pay much attention owing to low solubility of these materials. Between InAs, GaAs, and AlGaAs, InAs was the most toxic material to the lung followed by GaAs and AlGaAs when given intratracheally. This was probably due to difference in the toxicity of the counter-element of arsenic in semiconductor materials, such as indium, gallium, or aluminium, and not arsenic itself. It appeared that indium, gallium, or aluminium was toxic when released from the particles, though the physical character of the particles also contributes to toxic effect. Although there is no evidence of the carcinogenicity of InAs or AlGaAs, GaAs and InP, which are semiconductor materials, showed the clear evidence of carcinogenic potential. It is necessary to pay much greater attention to the human exposure of semiconductor materials.

Aluminum Compounds↗
PubMed1977

The gallium melting-point standard: a determination of the liquid-solid equilibrium temperature of pure gallium on the International Practical Temperature Scale of 1968.

The sharpness and reproducibility of the gallium melting point were studied and the melting temperature of gallium in terms of IPTS-68 was determined. Small melting-point cells designed for use with thermistors are described. Nine gallium cells including three levels of purity were used in 68 separate determinations fo the melting point. The melting point of 99.99999% pure gallium in terms of IPTS-68 is found to be 29.771(4) +/- 0.001(4) degree C; the melting range is less than 0.0005 degree C and is reproducible to +/- 0.0004 degree C.

Freezing↗
PubMed2005

The reactivity of gallium-(I), -(II) and -(III) heterocycles towards Group 15 substrates: attempts to prepare gallium-terminal pnictinidene complexes.

The reactivity of a series of Ga(I), Ga(II) and Ga(III) heterocyclic compounds towards a number of Group 15 substrates has been investigated with a view to prepare examples of gallium-terminal pnictinidene complexes. Although no examples of such complexes were isolated, a number of novel complexes have been prepared. The reactions of the gallium(I) N-heterocyclic carbene analogue, [K(tmeda)][:Ga{[N(Ar)C(H)](2)}] (Ar = 2,6-diisopropylphenyl) with cyclo-(PPh)(5) and PhN[double bond, length as m-dash]NPh led to the unusual anionic spirocyclic complexes, [{kappa(2)P,P'-(PhP)(4)}Ga{[N(Ar)C(H)](2)}](-) and [{kappa(2)N,C-PhNN(H)(C(6)H(4))}Ga{[N(Ar)C(H)](2)}](-), via formal reductions of the Group 15 substrate. The reaction of the digallane(4), [Ga{[N(Ar)C(H)](2)}](2), with (Me(3)Si)N(3) afforded the paramagnetic, dimeric imido-gallane complex, [{[N(Ar)C(H) ](2)}Ga{mu-N(SiMe(3))}](2), via a Ga-Ga bond insertion process. In addition, the new gallium(III) phosphide, [GaI{P(H)Mes*}{[N(Ar)C(H)](2) }], Mes* = C(6)H(2)Bu(t)(3)-2,4,6; was prepared and treated with diazabicycloundecane (DBU) to give [Ga(DBU){P(H)Mes*}{[N(Ar)C(H)](2)}], presumably via a gallium-terminal phosphinidene intermediate, [Ga{[double bond, length as m-dash]PMes*}{[N(Ar)C(H)](2) }]. The possible mechanisms of all reactions are discussed, all new complexes have been crystallographically characterised and all paramagnetic complexes have been studied by ENDOR and/or EPR spectroscopy.

Journal Article↗
PubMed2002

Siting of antimony dopants and gallium in Ba(8)Ga(16)Ge(30) clathrates grown from gallium flux.

A series of antimony-doped Ba(8)Ga(16)Ge(30) clathrates was grown as large crystals from gallium flux. These compounds form in the cubic space group Pm(-)3n, with the unit cell parameter varying from 10.784(5) to 10.9008(6) A as the amount of GaSb substituting for germanium atoms in the framework is increased. It was found that more antimony than extra gallium was incorporated into the material and that a specific site (the 24k Wyckoff site) was favored by this element. (71)Ga NMR was carried out to determine the siting of gallium; it fills the 6c site preferentially.

Journal Article↗