Metallomics related to gallium compounds: biochemical and xenobiochemical aspects

Zeno Gârban, Radu Silaghi-Dumitrescu, Gabriela Gârban, Adina Avacovici, Nicoleta Hădărugă, Cornel Baltă, George-Daniel Ghibu, Cristina Bischin, Olga-Alina Rada


Issues concerning the chemical compounds studied in the framework of metallomics are of interest both for biochemistry – domain dealing with the metabolization of nutrients and xenobiochemistry – a subsequent domain of biochemistry dealing with the biodegradation of xenobiotics. In this context, reviewed here are in vivo and in vitro data on inorganic and organo-metallic compounds of gallium (Ga), ranging from cellular and molecular biology, to biochemistry and pathobiochemistry, and to pharmacology and related to homeostasis and nutrient degradation.


gallium compounds – biochemistry; xenobiochemistry; biomedical effects; in vivo; in vitro

Full Text:



Alama Angela, Tasso B., Novelli Federica, Sparatore F. – Novel organotins as antitumor agents, Drug Discovery, 2009, 6, 50-53.

Aoki Y., Lipsky M.M., Fowler B.A. - Alteration in protein synthesis in primary cultures of rat kidney proximal tubule epithelial cells by exposure to gallium, indium, and arsenite. Toxicol. Appl. Pharmacol., 1990, 106, 462–468.

Baes C.F. Jr., Mesmer R.E. - The Hydrolysis of Cations, Wiley, New York, 1976.

Bernstein L. - Mechanism of therapeutic activity for gallium, Pharmacological Reviews, 1998, 50(4), 665-682.

Bernstein L.R., Tanner T., Godfrey Claire, Noll B. – Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium bioavailability, Metal-based Drugs, 2000, 7 (1), 33-47.

Bernstein L.R. – 31Ga therapeutic gallium compounds, pp.259-277, in „Metallotherapeutic drugs and metal-based diagnostic agents : The use of metals in medicine” (Gielen M., Tiekink E.R.T., Eds.) , J.Wiley and Sons Ltd., Chichester, 2005.

Bockman R.S., Boskey A.L., BlumenthalN.C., Alcock N.W., Warrell R.P., Jr. - Gallium increases bone calcium and crystalline perfection of hydroxyapatite. Calcif. Tissue Int., 1986, 39, 376-381.

Brucer M., Andrews G.A., Bruner H.D. – A study of gallium, Radiology, 1953, 61, 534-536.

Bruijnincx P.C., Sadler P.J. - New trends for metal complexes with anticancer activity, Curr. Opin. Chem. Biol., 2008,12(2), 197-206

Bruner H.D., Hayes R.L., Perkinson J.D. Jr. - A study of gallium 72: X - Preliminary data on gallium 67. Radiology, 1953, 61, 602–611.

Chen D., Frezza M., Shakya R., Cu Q.C., Milacic V., Verani C.N., Dou Q.P. - Inhibition of the Proteasome Activity by Gallium(III) Complexes Contributes to Their Anti–Prostate Tumor Effects. Cancer Res. 2007; 67(19), 9258-9265.

Chitambar C.R., Zivkovic Z. - Inhibition of hemoglobin production by transferrin–gallium. Blood, 1987, 69, 144–9.

Chitambar C.R. - Gallium nitrate for the treatment of non-Hodgkin's lymphoma., Expert.Opin.Investing Drugs, 2004, 13(5), 531-541.

Chitambar C.R. - Medical applications and toxicities of gallium compounds, Int.J. Res. Public Health, 2010, 7, 2337-2361

Chua M.S., Berstein L.R., Li R., So S.K.S. - Gallium maltolate is a promising chemotherapeutic agent for the tretment of hepatocellular carcinoma, Anticancer Res., 2006, 26, 1739-1744.

Collery P., Millart H., Lamiable D., Vistelle R., Rinjard P., Tran G., Gourdier B., Cossart C., Bouana J.C., Pechery C. - Clinical pharmacology of gallium chloride after oral administration in lung cancer patients. Anticancer Res., 1989, 9, 353-356.

Collery P., Morel M., Desoize B., Millart H., Perdu D., Prevost A., Vallerand H., Pechery C., Choisy H., Etienne J.C. - Combination chemotherapy with cisplatin, etoposide and gallium chloride for lung cancer: individual adaptation of doses. Anticancer Res., 1991, 11, 1529-1532.

Collery P., Millart H., Choisy H., Blanchot G., Leroy A., Anghileri L.J. - Dose-effect of GaCl3, orally administered, on gallim, magnesium, calcium and iron concentration in tumour and kidneys of mammary adenocarcinoma-bearing mice, Anticancer Res., 1992, 12, 1920-1921.

Collery P., Pechery C. - Clinical experience with tumorinhibiting gallium complexes, pp. 249-258, in „Metal Complexes in Cancer Chemotherapy” (Keppler B.K., Ed.), Weinheim V.C.H., 1993.

Collery P., Domingo J.L., Keppler B.K. - Preclinical toxicology and tissue gallium distribution of a novel antitumor gallium compound: tris (8-quinolinolato) gallium (III), Anticancer Res., 1996, 16, 687-91.

Collery P., Keppler B., Madoulet Claudie, Desoize B. - Gallium in cancer tratment, Critical Review in Oncology/Hematology, 2002, 42, 283-296.

Davies N.P., Rahmanto Y.S., Chitambar C.R., Richardson D.R. - Resistance to the Antineoplastic Agent Gallium Nitrate Results in Marked Alterations in Intracellular Iron and Gallium Trafficking: Identification of Novel Intermediates. The Journal Of Pharmacology And Experimental Therapeutics, 2006, 317, 153–162.

Desoize B. – Metals and metal compounds in cancer treatment, Anticancer Res., 2004, 24, 1529-1544.

Dobrov A, Arion V.B., Kandler N., Ginzinger W., Jakupec M.A., Rufin´ska A., Graf von Keyserling N., Galanski M., Kowol C., Keppler B.K., - The First Metal-Based Paullone Derivative with High Antiproliferative Activity in Vitro. Inorg. Chem. 2006, 45, 1945-1950.

Dreicer R., Propert K.J., Roth B.J., Einhorn L.H., Loehrer P.J. - Vinblastine, ifosfamide, and gallium nitrate—an active new regimen in patients with advanced carcinoma of the urothelium. A phase II trial of the Eastern Cooperative Oncology Group (E5892). Cancer, 1997, 79, 110–114.

Dudley H.C., Maddox G.E. - Deposition of radio gallium (Ga72) in skeletal tissues. J. Pharmacol. Exp. Ther., 1949, 96, 224–227.

Dudley H.C., Munn J.I., Henry K.E. - Studies of the metabolism of gallium. J. Pharmacol. Exp. Ther., 1950, 98, 105–110.

Edwards C.L., Hayes R.L. - Tumor scanning with 67Ga citrate . J. Nucl. Med., 1969, 10,103-105.

Fischer-Fodor Eva - manuscript submitted

Flora S.J., Tripathi N. - Hepatic and renal metallothionein induction following single oral administration of gallium arsenide in rats. Biochem Mol. Biol. Int., 1998, 45(6), 1121-1127.

Frezza M., Verani C.N., Di Chen D., Dou Q.P. - The Therapeutic Potential of Gallium-Based Complexes in Anti-Tumor Drug Design. Letters in Drug Design & Discovery, 2007, 4, 311-317.

Galanski, M. Arion V.B., Jakupec M.A., Keppler B.K. - Recent Developments in the Field of Tumor-Inhibiting Metal Complexes. Current Pharmaceutical Design, 2003, 9, 2078-2089.

Gârban Gabriela, Nicola T., Baltă C., Gârban Z., Hădărugă Nicoleta, Mitar Carmen, Simiz Eliza, Ghibu G.-D., Rada Olga-Alina - Chronobiological characteristics of some hematology parameters induced by gallium, pp.248-251, „The International Symposium on Analytical and Environmental problems, with special emphasis on heavy metal ions as contaminants”, (Ed. Z. Galbacs), Publ. by SZAB Szeged, 2012.

Gârban Z., Dancău G., Daranyi Gabriela, Erdelean R., Văcărescu G., Precob V., Eremia Iulia, Udrişte C. - Implication of chronobiochemistry-metabolism relationship in the induction of homeostasis changes. I. The action of cis-platinum on hepatic DNA biosynthesis and on some serum metabolites in rats, Rev. roum. Biochim., 1989, 26(2), 107-117.

Gârban Z., Carţiş Ioana, Avacovici Adina, Moldovan I. - Comparative aspects between the interaction of deoxyribonucleic acid with some cytostatic drugs: Particularisation for the action with cis-platinum and cyclophosphamide. I. Investigations in vivo on experimental animals, pp.1118-1125, in Mengen- und Spurenelemente, 20. Arbeitstagung 2000, Friedrich-Schiller-Universität Jena (Hrsg. Anke M. et al.); Verlag Harald Schubert, Leipzig, 2000

Gârban Z. – Influence of metals on deoxyribonucleic acid, Chap. 7 pp. 401-414 in “Elements and their Compounds in the Environment: Occurrence, Analysis and Biological Relevance” Vol. I General Aspects, (Eds. Merian E., Anke M., Ihnat M., Stoeppler M.), 2nd edition, Wiley-VCH Verlag GmbH & Co KgaA, Weinheim, 2004.

Gârban Z. - Biochimie: Tratat comprehensiv. Vol. IV.Xenobiochimie, ediţia 2-a, Editura Didactică şi Pedagogică R.A., Bucureşti, 2007 a.

Gârban Z., Gârban Gabriela, Ghibu G.D. – The importance of deoxyribonucleic acid adducts in biochemistry and xenobiochemistry, Revista de Chimie, 2007 b, 58(5), 456-460.

Gielen M., Tiekink E.R.T. (Eds.) – Metallotherapeutic drugs and metal-based diagnostic agents. The use of metals in medicine, J. Wiley and Sons Ltd., Chichester, 2005.

Gomez-Ruiz S., Gallego Beatriz, Kaluderovic R. Milena, Kommera H., Hey-Hawkins Evamarie, Pasche R., Kaluderovic N.G. – Novel gallium (III) complexes containing phtalolyl derivatives of neutral aminoacids with apoptotic activity in cancer cells, J. Organomet. Chem., 2009, 694, 2191-2197.

Hacht B. - Gallium (III) ion hydrolisys under physiological conditions, Bull. Korean Chem. Soc, 2008, 29(2), 372-376.

Haiduc I., Zuckermann J.J. – Basic Organometallic Chemistry, Walter de Gruyter, Berlin, 1985.

Haiduc I., Silvestru C. – Organometallics in Cancer Chemotherapy, Vol. I, Main Group Metal Compounds, CRC Press Inc., Boca Raton, FL, 1989.

Haiduc I. – Metals in medicine : past, present, future, pp. 35-42, in „Metal Elements in Environment, Medicine and Biology”, Tome II (Eds. Gârban Z., Drăgan P.), Publishing House Eurobit, Timişoara, 1996.

Haiduc I., Silaghi-Dumitrescu I., Gârban Z., Fischer-Fodor Eva, Silaghi-Dumitrescu R. - Metallomics, pp. 5-14, in „Metal Elements in Environment, Medicine and Biology”, Tome VIII (Eds. Silaghi-Dumitrescu I., Gârban Z., Drăgan P.), Publishing House Eurobit, Timişoara, 2008.

Haraguchi H. – Metallomics as integrated biometal science, J. Anal. At. Spectrom., 2004, 19, 5-14.

Hart M.M., Adamson R.H. - Antitumor activity and toxicity of salts of inorganic group 3a metals: aluminum, gallium, indium, and thallium. Proc. Natl. Acad. Sci. USA., 1971, 68, 1623-1626.

Hart M.M., Smith C.F., Yancey S.T., Adamson R.H. - Toxicity and antitumor activity of gallium nitrate and periodically related metal salts. J. Natl .Cancer Inst., 1971, 47, 1121-1127.

Hayes R.L., Rafter J.J., Byrd B.L., Carlton J.E. - Studies of the in vivo entry of Ga-67 into normal and malignant tissue. J. Nucl .Med., 1981, 22, 325-332.

Hedley D.W., Tripp E.H., Slowiaczek P., Mann G.J. - Effect of gallium on DNA synthesis by human T-cell lymphoblasts. Cancer Res., 1988, 48, 3014–3018.

Hofheinz R.D., Dittrich C., Jakupec M.A., Drescher A., Jaehde U., Gneist M., Graf von K.N., Keppler B.K., Hochhaus A. - Early results from a phase I study on orally administered tris(8-quinolinolato)gallium(III) (FFC11, KP46) in patients with solid tumors - a CESAR study (Central European Society for Anticancer Drug Research—EWIV) Int. J. Clin. Pharmacol. Ther., 2005, 43, 590–591.

Jakupec M.A., Galanski M., Arion V.B, Hartinger C.G., Keppler B.K. - Antitumour metal compounds: more than theme and variations. Dalton Trans., 2008, 183–194.

Jakupec M.A., Keppler B.K. - Gallium in cancer treatment. Curr. Top. Med. Chem., 2004, 4, 1575–1583.

Jenis L.G., Waud C.E., Stein G.S., Lian J.B., Baran D.T. – Effect of gallium in vitro and in normal rats, J. Cell Biochem., 1993, 52(3), 330-336.

Kolesar J.M., Schelman W.R., Geiger P.G., Holen K.D., Traynor A.M., Alberti D.B., Thomas J.P., Chitambar C.R., Wilding G., Antholine W.E. - Electron paramagnetic resonance study of peripheral blood mononuclear cells from patients with refractory solid tumors treated with Triapine®. J Inorg Biochem., 2008,102(4), 693-8.

Kowol C.R., Trondl R., Heffeter P., Arion V.B., Jakupec M.A., Roller A., Galanski M., Berger W., Keppler B.K. - Impact of Metal Coordination on Cytotoxicity of 3-Aminopyridine-2-carboxaldehyde Thiosemicarbazone (Triapine) and Novel Insights into Terminal Dimethylation. J. Med. Chem., 2009, 52(16), 5032–5043.

Lenglet Gaelle, Depauw Sabine, Mendy-Belaiche Denise, David-Cordonnier Marie-Helene – DNA helix destabilization by alkylating agents : From covalent bonding to DNA repair, pp.97-124, in „Selected topics in DNA repair” (Clark C.C., Ed.), InTech Publisher, California, 2011.

Levaditi C., Bardet J., Tchakirian A., Vaisman A.- Comptes Rendus de l’Academie des Sciences, Series D, 1931, 192, 1142–1143 – cited by Bernstein (2005).

Manfait M., Collery P. - Etude in vitro par spectroscopie Raman de la conformation d'un ADN sous l'influence des ions magnésium et gallium. Magnesium Bull., 1984, 4, 153-155.

Martell A.E., Hancock R.D. - Metal Complexes in Aqueous Solution, Plenum Press, New York, 1996.

Moskalyk R.R. - Gallium: the backbone of the electronics industry, Minerals Engineering, 2003, 16 (10), 921-929.

Murphy P.J. - Xenobiotic metabolism: a look from the past to the future, Drug. Metab. Dispos., 2001, 29(6), 779-780.

Nelson B., Hayes R.L., Edwards C.L., Kniseley R.M., Andrews G.A. - Distribution of gallium in human tissues after intravenous administration. J. Nucl. Med., 1972, 13, 92–100.

Newman R.A., Brody A.R., Krakoff I.H. – Gallium nitrate (NSC-15200) induced toxicitiy in the rat : a pharmacologic, histopathologic and microanalytical investigation, Cancer, 1979, 44 (5), 1728-1740.

Nordberg G.F., Fowler B.A., Nordberg Monica, Friberg L. – Handbook on the toxicology of metals, 3rd edition, Elsevier, San Diego-London, 2007.

Ortega R., Suda A., Deves G. - Nuclear microprobe imaging of gallium nitrate in cancer cells, Nucler Instruments and Methods in Physics Research Section B : Beam Interactions with Materials and Atoms, 2003, 210, 364-367.

Otsuki H., Brunetti A., Owens E.S., Finn R.D., Blasberg R.G. - Comparison of iron-59, indium-111, and gallium-69 transferrin as a macromolecular tracer of vascular permeability and the transferrin receptor. J. Nucl. Med., 1989, 30, 1676–1685.

Sadler P.J. – Bioinorganic Chemistry (Structure and Bonding), Springer-Verlag Berlin and Heidelberg GmbH & Co. K, 1991.

Schomäcker K., Franke W.-G., Henke E., Fromm W.-D., Maka G., Beyer G.-J. - The influence of isotopic and nonisotopic carriers on the biodistribution and biokinetics of M31-citrate complexes. Eur. J. Nucl. Med., 1986, 11, 345–349.

Schrautzer G.N. (Ed.) – Inorganic and Nutritional Aspects of Cancer, Proceedings of the 1st Conference of the International Association of Bioinorganic Scientists, California, Jan. 3-5, 1977, Plenum Press, New York-London, 1977.

Shakya R., Peng F., Liu J., Heeg M.J., Verani C.N. - Synthesis, Structure, and Anticancer Activity of Gallium(III) Complexes with Asymmetric Tridentate Ligands: Growth Inhibition and Apoptosis Induction of Cisplatin-Resistant Neuroblastoma Cells. Inorg. Chem. 2006, 45, 6263-6268.

Shannon R.D. - Revised effective ionic radii and systematic studies of interatomic distances in halides and chalcogenides. Acta Crystallographica, 1976, A32, 751–767.

Sharma V., Crankshaw, C.L. Piwnica-Worms D. - Effects of Multidrug Resistance (MDR1) P-Glycoprotein Expression Levels and Coordination Metal on the Cytotoxic Potency of Multidentate (N4O2) (Ethylenediamine)bis[propyl(R-benzylimino)]metal(III) Cations. J. Med. Chem. 1996, 39, 3483-3490.

Sigel Astrid, Sigel H., Sigel R.K.O. (Eds) – Metal Ions in Life Sciences, Vol.8, Metal Ions in Toxicology, Effects, Interactions, Interdependencies, RSC (Royal Society of Chemistry) Publishing Cambridge, 2011

Silaghi-Dumitrescu R. – unpublished data, 2012

Stojiljkovic I., Kumar V., Srinivasan N. - Non-iron metalloporphyrins: potent antibacterial compounds that exploit haem/Hb uptake systems of pathogenic bacteria. Mol. Microbiol., 1999, 31, 429-442.

Szpunar J. – Advances in analytical methodology for bioinorganic speciation analysis : metallomics, metalloproteomics and heteroatom-tagged proteomics and metabolomics, The Analyst, 2005, 130, 442-465.

Tajmir-Riahi H.A., Naoui M., Ahmad R. - A comparative study of calf–thymus DNA binding trivalent Al, Ga, Cr and Fe ions in aqueous solution. pp. 98-101, in „Metal ions in biology and medicine”, Vol. 2 (Anastassopoulou J., Collery P., Etienne J.C., Theophanides T. et al., Eds.), John Libbey Eurotext, Paris, 1992.

Thiel M., Schilling T., Gey D.C., Ziegler R., Collery P., Keppler B.K. - Relevance of tumor models for anticancer drug development. Contribution to Oncology. 1999, 54, 439-443.

Tsan M.F. - Mechanism of gallium-67 accumulation in inflammatory lesions. J. Nucl. Med., 1985, 26, 88–92.

Vălean Ana-Maria, Gómez-Ruiz S., Lönnecke P., Silaghi-Dumitrescu I., Silaghi-Dumitrescu Luminiţa, Hey-Hawkins Evamarie – Stabilisation of an inorganic digallane by the phosphinobisthiolato P,S,S pincer Ligand PPh(2-SC6H4)2 , New J.Chem., 2009, 33, 1771-1779.

Vistelle R., Collery P., Millart H. - In vivo distribution of gallium in healthy rats after oral administration and interactions with iron, magnesium and calcium, Trace Elem. Med., 1989, 6, 27-32.

Wakley G.K., Garand J., Brown D., Szukalski B.W., Bell N.H., Turner R.T. – Effects of gallium on bone in the rat, J. Bone Miner. Res., 1992, 7, 11-19.

Warrell R.P., Jr., Issacs M., Alcock N.W., Bockman R.S. - Gallium nitrate for treatment of refractory hypercalcemia from parathyroid carcinoma - Ann. Intern. Med., 1987, 107, 683-686.

Warrell R.P., Jr. - Gallium for treatment of bone diseases, pp. 1253-1265, in “Handbook of Metal-Ligand Interactions in Biological Fluids - Bioinorganic Medicine”, Vol. 2, Berthon G. (Ed.), Marcel Dekker, Inc., New York, 1995

Warrell R.P., Jr. - Gallium for treatment of bone disease, pp 1253–1265, in Handbook of Metal-Ligand Interactions in Biological Fluids, Bioinorganic Medicine. Vol.2 (Ed. Berthon G.), Marcel Dekker, New York, 1995.

Webb D.R., Sipes I. G., Carter D.E. - In vitro solubility and in vivo toxicity of gallium arsenide. Toxicol. Sppl. Pharmacol., 1984, 76, 96-104.

Webb D.R., Wilson S.E., Carter D.E. - Pulmonary clearance and toxicity of respirable gallium arsenide particulates intratracheally instilled into rats. Am. Ind. Hyg. Assoc. J., 1987, 48, 660–667.

.Weiner R.E., Schreiber G.J., Hoffer P.B. - In vitro transfer of Ga-67 from transferrin to ferritin. J. Nucl. Med, 1983, 20, 608–614.

Weiner R.E. - Role of phosphate-containing compounds in the transfer of indium-111 and gallium-67 from transferrin to ferritin. J. Nucl. Med., 1989, 30,70–79.

Williams D.R. – The metals of life: the solution chemistry of metal ions in biological systems, van Nostrand-Reinhold, London, 1971.

Williams R.J.P. – Chemical selection of elements by cells, Coordination Chemistry Reviews, 2001, 216-217, 583-595.

Yang J.L., Chen H.C. - Effects of gallium on common carp (Cyprinus carpio): acute test, serum biochemistry, and erytrocyte morphology, Chemosphere, 2003, 53,877-882.

Yang M., Chitambar C.R. - 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 Radic Biol Med. 2008, 45(6), 763–772.

Yang M., Kroft S.H., Chitambar C.R. - 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, Mol. Cancer Ther., 2007, 6, 633–643.

*** - W.H.O. International Agency For Research on Cancer, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 86, Cobalt in Hard Metals and Cobalt Sulfate, Gallium Arsenide, Indium Phosphide and Vanadium Pentoxide, Lyon, 2006

*** - NTP Toxicology and Carcinogenesis Studies of Gallium Arsenide (CAS No. 1303-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Natl. Toxicol. Program. Tech. Rep. Ser., 2000, 492, 1-306 - cited by Chitambar (2010).



  • There are currently no refbacks.

Copyright (c) 2016 Zeno Gârban, Radu Silaghi-Dumitrescu, Gabriela Gârban, Adina Avacovici, Nicoleta Hădărugă, Cornel Baltă, George-Daniel Ghibu, Cristina Bischin, Olga-Alina Rada

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.