title: Inhibition of steroid sulphatase activity by steroidal methylthiophosphonates: potential therapeutic agents in breast cancer.
abstract: The hydrolysis of steroid sulphates, by steroid sulphatase, is an important source of oestrogenic steroids (oestrone, oestradiol and 5-androstene-3 beta,17 beta-diol) which are found in tumours. In the present study, we have examined the effect of dehydroepiandrosterone-3-O-methylthiophosphonate (DHA-3-MTP), pregnenolone-3-O-methylthiophosphonate (pregnenolone-3-MTP) and cholesterol-3-O-methylthiophosphonate (cholesterol-3-MTP) on the inhibition of oestrone sulphatase as well as DHA sulphatase activities in intact MCF-7 breast cancer cells and in placental microsomes. All three methylthiophosphonates significantly (P < 0.01) inhibited the hydrolysis of oestrone sulphate (E1 S) in intact MCF-7 cells (31-85% inhibition at 1 microM and 53-97% inhibition at 10 microM). Significant inhibition of DHA sulphatase was also achieved. At a concentration of 50 microM, all three compounds inhibited the hydrolysis of dehydroepiandrosterone sulphate (DHAS) by > 95%. Using human placental microsomes, the Km and Vmax of E1S were determined to be 8.1 microM and 43 nmol/h/mg protein. The corresponding Ki values for DHA-3-MTP, pregnenolone-3-MTP and cholesterol-3-MTP were found to be 4.5, 1.4 and 6.2 microM, respectively. Such inhibitors which are resistant to metabolism may have considerable potential as therapeutic agents and may have additional advantage over aromatase inhibitors in also reducing tumour concentrations of the oestrogenic steroid, 5-androstene-3 beta,17 beta-diol, by inhibiting the hydrolysis of DHAS.
authors.affiliation: Unit of Metabolic Medicine, St Mary's Hospital Medical School, Imperial College of Science, Technology and Medicine, London, England.
authors.forename: A
authors.initials: A
authors.lastname: Purohit
authors.forename: N M
authors.initials: NM
authors.lastname: Howarth
authors.forename: B V
authors.initials: BV
authors.lastname: Potter
authors.forename: M J
authors.initials: MJ
authors.lastname: Reed
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001192:Arylsulfatases / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008861:Microsomes / Q000201:enzymology; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011284:Pregnenolone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D043266:Steryl-Sulfatase; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C087186:dehydroepiandrosterone-3-O-methylthiophosphonate; C087187:pregnenolone-3-O-methylthiophosphonate; C087188:cholesterol-3-O-methylthiophosphonate; D003687:Dehydroepiandrosterone; D011284:Pregnenolone; D002784:Cholesterol; D001192:Arylsulfatases; D043266:Steryl-Sulfatase