Continuous infusion gallium nitrate for patients with advanced refractory urothelial tract tumors

Seidman, Andrew D.; Scher, Howard I.; Heinemann, Murk Hein; Bajorin, Dean F.; Sternberg, Cora N.; Dershaw, D. David; Silverberg, Mary; Bosl, George J.

doi:10.1002/1097-0142(19911215)68:12<2561::aid-cncr2820681205>3.0.co;2-g

Cited by 81 publications

(15 citation statements)

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“…There are currently three main agents in clinical studies. The first is based on gallium nitrate, which interferes with the release of iron from endocytic vesicles, the second is iron chelation, and the third treatment is based on the use of mAbs or small molecules against transferrin or the TfR (25)(26)(27)(28)(29)(30)(31)(32)(33). In this study, we showed that two different anti-TfR mAbs A27.…”

Section: Discussionmentioning

confidence: 99%

Effects of Transferrin Receptor Blockade on Cancer Cell Proliferation and Hypoxia-Inducible Factor Function and Their Differential Regulation by Ascorbate

2006

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Cellular iron is needed for cell survival and hydroxylation of hypoxia-inducible factor-1A (HIF-A) by prolyl hydroxylases (PHD). One mechanism of iron uptake is mediated by the cell surface transferrin receptor (TfR). Because iron is required for cell growth and suppression of HIF-A levels, we tested the effects of the two anti-TfR monoclonal antibodies (mAb) E2.3 and A27.15 on growth of breast cancer cells and induction of HIF-A and hypoxia-regulated genes. Treatment with both mAbs together synergistically inhibited cell proliferation in a doseresponsive manner by up to 80% following 8 days of exposure, up-regulated HIF-1A and HIF transcription targets, downregulated TfR expression, and down-regulated cellular labile iron pool by 60%. Because combined treatment with anti-TfR mAbs resulted in the up-regulation of the hypoxia pathway, which may increase tumor angiogenesis, we analyzed the effects of ascorbate on cell viability and HIF-1A levels in cells treated with both anti-TfR mAbs together, as ascorbate has been shown to be required by PHD enzymes for full catalytic activity. Ascorbate at physiologic concentrations (25 Mmol/L) suppressed HIF-1A protein levels and HIF transcriptional targets in anti-TfR mAb-treated cells but did not suppress the antiproliferative effect of the mAbs. These results indicate that the addition of ascorbate increased the activity of the PHD enzymes in down-regulating HIF but not the proliferation of iron-starved anti-TfR mAb-treated cells. The use of anti-TfR mAbs and ascorbate in inhibiting both cell proliferation and HIF-1A and angiogenesis under normoxic conditions may be of therapeutic use. (Cancer Res 2006; 66(5): 2749-56)

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Section: Discussionmentioning

confidence: 99%

Effects of Transferrin Receptor Blockade on Cancer Cell Proliferation and Hypoxia-Inducible Factor Function and Their Differential Regulation by Ascorbate

2006

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“…Gallium (Ga) is group IIIa metal salt with significant activity against bladder cancer and lymphoma (Warrell et al, 1983;Chitambar and Seligman, 1986;Chitambar et al, 1988;Crawford et al, 1991;Seidman et al, 1991;Seligman and Crawford, 1991). Moreover, gallium, as its radioisotope 67 Ga, is widely used clinically for the effective radio imaging of tumors (Chitambar, 2004).…”

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confidence: 84%

Resistance to the Antineoplastic Agent Gallium Nitrate Results in Marked Alterations in Intracellular Iron and Gallium Trafficking: Identification of Novel Intermediates

Davies¹,

Rahmanto²,

Chitambar³

et al. 2005

J Pharmacol Exp Ther

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“…15 Clinical trials have demonstrated activity against some malignancies, including epithelial ovarian carcinoma, non-squamous cell carcinoma of the cervix, bladder cancer 16,17 and non-Hodgkin's lymphoma. Other clinical trials under way include studies of sarcoidosis and rheumatoid arthritis.…”

Section: Introductionmentioning

confidence: 99%

Study of gallium(III) nitrate hydrate and aqueous solutions: Raman spectroscopy and ab initio molecular orbital calculations of gallium(III) water clusters

Rudolph

Pye

Irmer³

2002

J Raman Spectroscopy

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Raman spectra of aqueous Ga(III) perchlorate and nitrate solutions were measured at room temperature. From Ga(ClO 4 ) 3 solutions, a strongly polarized band at 526 cm −1 and two depolarized modes at 430 and 328 cm −1 were assigned to n 1 (a 1g ), n 2 (e g ) and n 5 (f 2g ) of the hexaaquagallium(III) ion, [Ga(OH 2 ) 6 3+ ] (O h symmetry), respectively. The infrared active mode at 555 cm −1 was assigned to n 3 (f 1u ). The Raman spectroscopic data suggest that the hexaaquagallium(III) ion is thermodynamically stable in perchlorate solutions (no inner-sphere complex formation). In a supersaturated solution and in concentrated Ga(NO 3 ) 3 solutions most of the gallium(III) exists in the form of an outer-sphere ion pair, [Ga(OH 2 ) 6 3+ NO 3 − ], but a small amount of the gallium(III) occurs as an inner-sphere complex, [Ga(OH 2 ) 5 ONO 2 ] 2+ , which could be confirmed using Raman spectroscopy. Upon dilution, the fraction of the weak inner-sphere nitrato complex diminishes and only the outer-sphere complex is observable. Ab initio geometry optimizations and wavenumber calculations of [Ga(OH 2 ) 6 3+ ] were carried out at the Hartree-Fock and second order Møller-Plesset levels of theory, using various basis sets up to 6-31 + G * . The global minimum structure of the hexaaqua Ga(III) species corresponds to symmetry T h . The unscaled vibrational wavenumbers of the [Ga(OH 2 ) 6 3+ ] are reported. The unscaled vibrational wavenumbers of the GaO 6 unit are lower than the experimental values (∼15%). Scaling the wavenumbers reproduces only partially the measured values for the GaO 6 unit. The theoretical binding enthalpy for [Ga(OH 2 ) 6 3+ ] was calculated and accounts for ∼60% of the experimental single ion hydration enthalpy for Ga(III). Ab initio geometry optimizations and wavenumber calculations are also reported for a [Ga(OH 2 ) 18 3+ ] (Ga[6 + 12]) cluster with six water molecules in the first sphere and 12 water molecules in the second sphere. The global minimum occurs for T symmetry. Calculated wavenumbers of the gallium [6 + 12] cluster correspond well with the observed wavenumbers in solution. The n 1 GaO 6 (unscaled) mode occurs at 524 cm −1 , which is in good agreement with the experimental value. The theoretical binding enthalpy for [Ga(OH 2 ) 18 3+ ] was calculated and is slightly underestimated compared with the experimental single ion hydration enthalpy of Ga(III). The water molecules of the first sphere form strong H-bonds with water molecules in the second hydration shell because of the strong polarizing effect of the Ga(III) ion.

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Continuous infusion gallium nitrate for patients with advanced refractory urothelial tract tumors

Cited by 81 publications

References 3 publications

Effects of Transferrin Receptor Blockade on Cancer Cell Proliferation and Hypoxia-Inducible Factor Function and Their Differential Regulation by Ascorbate

Effects of Transferrin Receptor Blockade on Cancer Cell Proliferation and Hypoxia-Inducible Factor Function and Their Differential Regulation by Ascorbate

Resistance to the Antineoplastic Agent Gallium Nitrate Results in Marked Alterations in Intracellular Iron and Gallium Trafficking: Identification of Novel Intermediates

Study of gallium(III) nitrate hydrate and aqueous solutions: Raman spectroscopy and ab initio molecular orbital calculations of gallium(III) water clusters

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