title: Pharmaceutical development of the novel arsenical based cancer therapeutic GSAO for Phase I clinical trial.
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 50 mg/mL GSAO in 100 mM 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.
authors.affiliation: Cancer Research UK Formulation Unit, Strathclyde Institute for Pharmacy and Biomedical Sciences, Robertson Wing, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, Scotland, UK. Electronic address: moira.elliott@strath.ac.uk.
authors.forename: M A
authors.initials: MA
authors.lastname: Elliott
authors.affiliation: Cancer Research UK Formulation Unit, Strathclyde Institute for Pharmacy and Biomedical Sciences, Robertson Wing, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, Scotland, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Ford
authors.affiliation: Cancer Research UK Formulation Unit, Strathclyde Institute for Pharmacy and Biomedical Sciences, Robertson Wing, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, Scotland, UK.
authors.forename: E
authors.initials: E
authors.lastname: Prasad
authors.affiliation: Cancer Research UK Formulation Unit, Strathclyde Institute for Pharmacy and Biomedical Sciences, Robertson Wing, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, Scotland, UK.
authors.forename: L J
authors.initials: LJ
authors.lastname: Dick
authors.affiliation: Cancer Research UK Drug Development Office, Angel Building, 407 St. John Street, London, EC1V 4AD, England, UK.
authors.forename: H
authors.initials: H
authors.lastname: Farmer
authors.affiliation: Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Hogg
authors.affiliation: Cancer Research UK Formulation Unit, Strathclyde Institute for Pharmacy and Biomedical Sciences, Robertson Wing, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, Scotland, UK.
authors.forename: G W
authors.initials: GW
authors.lastname: Halbert
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D000975:Antioxidants / Q000737:chemistry; D001152:Arsenicals / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use*; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D004339:Drug Compounding; D004355:Drug Stability; D005612:Freeze Drying; D005978:Glutathione / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D005998:Glycine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010084:Oxidation-Reduction; D011199:Potentiometry; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors
chemical_list: C426645:4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide; D020533:Angiogenesis Inhibitors; D000975:Antioxidants; D001152:Arsenicals; D005978:Glutathione; D005998:Glycine