A phase 1 trial of intravenous 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) in patients with advanced solid tumours

Horsley, Laura; Cummings, Jeff; Middleton, Mark R.; Ward, Tim; Backen, Alison; Clamp, Andrew R.; Dawson, Martin D.; Farmer, Hayley; Fisher, Nita; Halbert, Gavin; Halford, Sarah; Harris, Adrian L.; Hasan, Jurjees; Hogg, Philip J.; Kumaran, G.; Little, Ross A.; Parker, Geoffrey; Potter, Paula; Saunders, Mark; Roberts, Caleb; Shaw, Danielle; Smith, Nigel; Smythe, Jon; Taylor, Andrew M.; Turner, Helen; Watson, Yvonne; Dive, Caroline; Jayson, Gordon C

doi:10.1007/s00280-013-2320-9

Cited by 35 publications

(27 citation statements)

References 23 publications

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“…However, PAO's high toxicity and nonselectivity for cancer cells over normal cells are drawbacks to be overcome in any drug development program. Recently, an analog of PAO (4‐( N ‐( S ‐glutathionylacetyl)amino)phenylarsonous acid) has been tested in phase I clinical trials for solid tumors that are refractory to standard therapy …”

Section: Introductionmentioning

confidence: 99%

“…Recently, an analog of PAO (4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid) has been tested in phase I clinical trials for solid tumors that are refractory to standard therapy. 30 It is now well-established that in human cancers, arsenic detoxification is performed by the GST/GSH detoxification system. However, the interaction of GSTP1-1 with arsenic-based drugs is surprisingly poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

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Glutathione transferase P1‐1 as an arsenic drug‐sequestering enzyme

et al. 2016

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Arsenic-based compounds are paradoxically both poisons and drugs. Glutathione transferase (GSTP1-1) is a major factor in resistance to such drugs. Here we describe using crystallography, X-ray absorption spectroscopy, mutagenesis, mass spectrometry, and kinetic studies how GSTP1-1 recognizes the drug phenylarsine oxide (PAO). In conditions of cellular stress where glutathione (GSH) levels are low, PAO crosslinks C47 to C101 of the opposing monomer, a distance of 19.9 Å , and causes a dramatic widening of the dimer interface by approximately 10 Å . The GSH conjugate of PAO, which forms rapidly in cancerous cells, is a potent inhibitor (K i 5 90 nM) and binds as a di-GSH complex in the active site forming part of a continuous network of interactions from one active site to the other. In summary, GSTP1-1 can detoxify arsenic-based drugs by sequestration at the active site and at the dimer interface, in situations where there is a plentiful supply of GSH, and at the reactive cysteines in conditions of low GSH.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glutathione transferase P1‐1 as an arsenic drug‐sequestering enzyme

et al. 2016

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“…GSAO [4-( N -( S -glutathionylacetyl)amino)phenylarsonous acid] and Darinaparsin (ZIO-101; S -dimethylarsino-GSH) are arsenic-based GSH-conjugates with demonstrated antitumor activity evaluated in clinical trials (Don et al, 2003; Dilda et al, 2005b; Diaz et al, 2008; Tsimberidou et al, 2009; Hosein et al, 2012; Horsley et al, 2013). For both drugs, extracellular γGT activity is an essential and limiting step in their activation into membrane permeable compounds (Dilda et al, 2008; Garnier et al, 2014).…”

Section: Glutathione S-derivatives Activated By γGt and Peptidasesmentioning

confidence: 99%

“…4-( N -( S -glutathionylacetyl)amino)phenylarsonous acid is a prospective cancer drug and has just completed a phase I dose escalation study in patients with solid tumors refractory to standard therapy (Horsley et al, 2013). Treatment was very well tolerated.…”

Section: Glutathione S-derivatives Activated By γGt and Peptidasesmentioning

confidence: 99%

“…In the case of GSAO, a reversible renal toxicity described in preclinical studies at the maximal tolerated dose was not observed in human during clinical Phase I (Horsley et al, 2013). Similarly, Darinaparsin, when employed in patients (Tsimberidou et al, 2009; Wu et al, 2010; Hosein et al, 2012) didn’t display any toxicity profile related to renal dysfunction at dose-limiting toxicity (DLT).…”

Section: Glutathione S-derivatives Activated By γGt and Peptidasesmentioning

confidence: 99%

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Glutathione S-conjugates as prodrugs to target drug-resistant tumors

Ramsay

Dilda

2014

Front. Pharmacol.

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Living organisms are continuously exposed to xenobiotics. The major phase of enzymatic detoxification in many species is the conjugation of activated xenobiotics to reduced glutathione (GSH) catalyzed by the glutathione-S-transferase (GST). It has been reported that some compounds, once transformed into glutathione S-conjugates, enter the mercapturic acid pathway whose end products are highly reactive and toxic for the cell responsible for their production. The cytotoxicity of these GSH conjugates depends essentially on GST and gamma-glutamyl transferases (γGT), the enzymes which initiate the mercapturic acid synthesis pathway. Numerous studies support the view that the expression of GST and γGT in cancer cells represents an important factor in the appearance of a more aggressive and resistant phenotype. High levels of tumor GST and γGT expression were employed to selectively target tumor with GST- or γGT-activated drugs. This strategy, explored over the last two decades, has recently been successful using GST-activated nitrogen mustard (TLK286) and γGT-activated arsenic-based (GSAO and Darinaparsin) prodrugs confirming the potential of GSH-conjugates as anticancer drugs.

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Dynamic contrast‐enhanced MRI for oncology drug development

Sung

Park

Choi

et al. 2016

Magnetic Resonance Imaging

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Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a promising tool for evaluating tumor vascularity, as it can provide vasculature-derived, functional, and quantitative parameters. To implement DCE-MRI parameters as biomarkers for monitoring the effect of antiangiogenic or vascular-disrupting treatment, two crucial elements of surrogate endpoint, ie, validation and qualification, should be satisfied. Although early studies have shown the accuracy and reliability of DCE-MRI parameters for evaluating treatment-driven vascular alterations, there have been an increasing number of studies demonstrating the limitations of DCE-MRI parameters as surrogate endpoints. Therefore, in order to improve the application of DCE-MRI parameters in drug development, it is necessary to establish a standardized evaluation method and to determine the correct therapeutics-oriented meaning of individual DCE-MRI parameter. In this regard, this article describes the biophysical background and data acquisition/analysis techniques of DCE-MRI while focusing on the validation and qualification issues. Specifically, the causes of disagreement and confusion encountered in the preclinical and clinical trials using DCE-MRI are presented in detail. Finally, considering these limitations, we present potential strategies to optimize implementation of DCE-MRI. J. Magn. Reson. Imaging 2016;44:251-264.

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A phase 1 trial of intravenous 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) in patients with advanced solid tumours

Abstract: The MTD of GSAO was 22.0 mg/m(2)/day. There was no biomarker evidence from DCE-MRI or circulating markers of angiogenesis of an anti-vascular effect of GSAO.

Cited by 35 publications

References 23 publications

Glutathione transferase P1‐1 as an arsenic drug‐sequestering enzyme

Glutathione transferase P1‐1 as an arsenic drug‐sequestering enzyme

Glutathione S-conjugates as prodrugs to target drug-resistant tumors

Dynamic contrast‐enhanced MRI for oncology drug development

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