Pharmaceutical development of the novel arsenical based cancer therapeutic GSAO for phase I clinical trial

Moira Elliott, S J Ford, E Prasad, L J Dick, H Farmer, P J Hogg, G W Halbert

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The novel organoarsenical GSAO, 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid, has potential anti-angiogenic capability with application in cancer where tumour metastasis relies on neo-vascularisation. As GSAO arsenic is trivalent, the arsenoxide moiety reacts with appropriately spaced cysteine residues on adenine nucleotide translocase (ANT) mitochondrial membrane protein. Molecular oxidation of the arsenic to the pentavalent structure, as in the degradant GSAA (4-(N-(S-glutathionylacetyl)amino) phenylarsonic acid), prevents sulphydryl interaction and risks abolition of activity. We report here on formulation studies aiming to produce a parenteral product with the primary objective of restricting GSAA transformation from GSAO to protect maximal potency of the molecule. Successful anti-oxidant strategy primarily came from pH control. The presence of glycine was proposed to form a stabilising five-membered oxazarsolidinone ring with arsenoxide and this was investigated using potentiometric assays. We report on these tritration studies identifying a pK(a) of 8.2 associated with an As-OH, but not confirming ring presence. An original clinical trial pharmaceutical was successfully realised by lyophilisation of 50mg/mL GSAO in 100mM glycine solution, pH 7 to obtain a 48-month shelf life for the freeze-dried vials. The Phase I clinical study is ongoing in patients with solid tumours refractory to standard therapy.
LanguageEnglish
Pages67-75
Number of pages9
JournalInternational Journal of Pharmaceutics
Volume426
Issue number1-2
DOIs
Publication statusPublished - 15 Apr 2012

Fingerprint

Arsenicals
Clinical Trials, Phase I
Arsenic
Glycine
ATP Translocases Mitochondrial ADP
Pharmaceutical Preparations
Amino Acids
Neoplasms
Freeze Drying
Mitochondrial Proteins
Mitochondrial Membranes
Oxidants
Cysteine
Membrane Proteins
Therapeutics
Clinical Trials
Neoplasm Metastasis
oxophenarsine

Keywords

  • phenylarsonous acid
  • cancer
  • lyophilisation
  • tumours

Cite this

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abstract = "The novel organoarsenical GSAO, 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid, has potential anti-angiogenic capability with application in cancer where tumour metastasis relies on neo-vascularisation. As GSAO arsenic is trivalent, the arsenoxide moiety reacts with appropriately spaced cysteine residues on adenine nucleotide translocase (ANT) mitochondrial membrane protein. Molecular oxidation of the arsenic to the pentavalent structure, as in the degradant GSAA (4-(N-(S-glutathionylacetyl)amino) phenylarsonic acid), prevents sulphydryl interaction and risks abolition of activity. We report here on formulation studies aiming to produce a parenteral product with the primary objective of restricting GSAA transformation from GSAO to protect maximal potency of the molecule. Successful anti-oxidant strategy primarily came from pH control. The presence of glycine was proposed to form a stabilising five-membered oxazarsolidinone ring with arsenoxide and this was investigated using potentiometric assays. We report on these tritration studies identifying a pK(a) of 8.2 associated with an As-OH, but not confirming ring presence. An original clinical trial pharmaceutical was successfully realised by lyophilisation of 50mg/mL GSAO in 100mM glycine solution, pH 7 to obtain a 48-month shelf life for the freeze-dried vials. The Phase I clinical study is ongoing in patients with solid tumours refractory to standard therapy.",
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Pharmaceutical development of the novel arsenical based cancer therapeutic GSAO for phase I clinical trial. / Elliott, Moira; Ford, S J; Prasad, E; Dick, L J; Farmer, H; Hogg, P J; Halbert, G W.

In: International Journal of Pharmaceutics, Vol. 426, No. 1-2, 15.04.2012, p. 67-75.

Research output: Contribution to journalArticle

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AU - Elliott, Moira

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AU - Prasad, E

AU - Dick, L J

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