title: Inhibition of steroid sulphatase activity via the percutaneous route: a new option for breast cancer therapy.
abstract: Steroid sulphatase (STS) inhibitors have been developed primarily for the treatment of hormone-dependent breast cancer, but may also have utility for the treatment of a number of androgen-dependent skin conditions. STS regulates the hydrolysis of steroid sulphates, such as oestrone sulphate (E1S) and dehydroepiandrosterone sulphate, (DHEAS). Liberated oestrone (E1) can be converted to biologically active oestradiol (E2) while dehydroepiandrosterone (DHEA) can undergo reduction to testosterone or aromatisation to E1. In this study the ability of the STS inhibitor STX64 (BN83495) and its N,N-dimethyl analogue (STX289) to inhibit liver and skin STS when applied orally or topically to nude mice was examined. Oral administration at 1 and 10 mg/kg resulted in almost complete inhibition of skin and liver STS. When applied topically to the dorsal neck region at 1.0 and 10 mg/kg not only skin but, unexpectedly, also liver STS was effectively inhibited. An investigation into the metabolism of these two compounds by HepG2 liver carcinoma cells, with high-performance liquid chromatography (HPLC) analysis, was also undertaken. In the presence of HepG2 cells a similar degree of desulphamoylation of STX64 (68%) or de-N, N-dimethylsulphamoylation of STX289 (66%) occurred over a 3h period. In the absence of cells, however, STX289 was resistant to de-N, N-dimethylsulphamoylation whereas STX64 was completely desulphamoylated, demonstrating the more favourable pharmaceutical profile of STX289 for development for topical application. It is concluded that both STX64 and STX289 are not only effective inhibitors of skin STS, but also liver STS when applied topically. These findings suggest that it may be possible to develop a formulation for the percutaneous administration of STS inhibitors, but also that this class of compound may have therapeutic potential for the treatment of a number of skin disorders.
authors.affiliation: Endocrinology and Metabolic Medicine and Sterix Ltd, Imperial College London, St. Mary's Hospital, London W2 1NY, UK.
authors.forename: A
authors.initials: A
authors.lastname: Purohit
authors.forename: S K
authors.initials: SK
authors.lastname: Chander
authors.forename: L W L
authors.initials: LW
authors.lastname: Woo
authors.forename: M F C
authors.initials: MF
authors.lastname: Parsons
authors.forename: R
authors.initials: R
authors.lastname: Jhalli
authors.forename: B V L
authors.initials: BV
authors.lastname: Potter
authors.forename: M J
authors.initials: MJ
authors.lastname: Reed
mesh_terms: D000279:Administration, Cutaneous; D000287:Administration, Topical; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology; D008745:Methylation; D051379:Mice; D008819:Mice, Nude; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013451:Sulfonic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C530264:STX289; D013451:Sulfonic Acids; C520511:irosustat; D043266:Steryl-Sulfatase