Gallium in cancer treatment

Collery, Philippe; Keppler, Bernhard K.; Madoulet, Claudie; Desoize, B

doi:10.1016/s1040-8428(01)00225-6

Cited by 234 publications

(229 citation statements)

References 63 publications

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“…Numerous gallium(III) complexes inhibit tumor growth and Ga was the second metal ion, after platinum to be administered to cancer patients in various clinical trials [1][2][3][4]. Ga is used in a wide variety of applications, such as medical imaging for some cancer types, infections and inflammatory diseases in form of 67 Ga(III) and 68 Ga(III) radiopharmaceuticals [5] and fluorescent Ga(III) compounds possibly in organic light-emitting diodes [6].…”

Section: Introductionmentioning

confidence: 99%

“…Remarkably, the simple salt Ga(III) nitrate exerts antineoplastic effects in particular for the treatment of lymphoma and bladder cancer and has a therapeutic effect in cancer-related hypercalcaemia (Ganite TM in clinical use) [3]. Orally administered Ga(III) salts are not sufficiently bioavailable.…”

Section: Introductionmentioning

confidence: 99%

“…Promising compounds are found to be the six-coordinate [1,2]. Both complexes can be administered orally, exhibit moderate side effects and can overcome Ga(III) nitrate resistance [3,7,8].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Comparative solution equilibrium studies of anticancer gallium(III) complexes of 8-hydroxyquinoline and hydroxy(thio)pyrone ligands

Enyedy

Dömötör

Varga

et al. 2012

Journal of Inorganic Biochemistry

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparative solution equilibrium studies of anticancer gallium(III) complexes of 8-hydroxyquinoline and hydroxy(thio)pyrone ligands

Enyedy

Dömötör

Varga

et al. 2012

Journal of Inorganic Biochemistry

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“…Gallium nitrate is metallodrug that has clinical activity in the treatment of non-Hodgkin's lymphoma and urothelial malignancies [1][2][3][4]. Several clinical trials conducted over the past two decades as well as more recent studies conducted in patients with lymphoma have confirmed its antineoplastic activity when used as a single agent or in combination with other chemotherapeutic drugs [5][6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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

Yang

Chitambar

2008

Free Radical Biology and Medicine

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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 dichlorodihydrofluoroscein (DCF) fluorescence, was seen after 1 -4 h 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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“…Inhibition of cellular proliferation by gallium is due in part to disruption of intracellular iron homeostasis, including an inhibition of the iron-dependent activity of ribonucleotide reductase (13 -15). Other mechanisms of cytotoxicity may also be involved but are less well defined (16,17).…”

Section: Introductionmentioning

confidence: 99%

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

Yang¹,

Kroft

Chitambar³

2007

Molecular Cancer Therapeutics

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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 galliumsensitive lymphoma cell lines developed by us. Galliumresistant 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. [Mol Cancer Ther 2007;6(2):633 -43]

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Gallium in cancer treatment

Cited by 234 publications

References 63 publications

Comparative solution equilibrium studies of anticancer gallium(III) complexes of 8-hydroxyquinoline and hydroxy(thio)pyrone ligands

Comparative solution equilibrium studies of anticancer gallium(III) complexes of 8-hydroxyquinoline and hydroxy(thio)pyrone ligands

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

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

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