Measurement of oestrone sulphatase activity in white blood cells to monitor in vivo inhibition of steroid sulphatase activity by oestrone-3-O-sulphamate.
Formation of oestrone via the sulphatase pathway is considered to be a major source of the oestrogen present in breast tumours. Several inhibitors of steroid sulphatase have now been developed for use in the treatment of postmenopausal women with breast cancer. In order to be able to monitor the extent and duration of the inhibition of oestrone sulphatase (E1-STS) readily, we have developed a method to measure the activity of this enzyme in white blood cells (WBCs). Hydrolysis of oestrone sulphate by E1-STS in WBCs was linear with respect to time and the volume of WBCs used. To examine whether the extent of inhibition of E1-STS activity in WBCs, by the inhibitor oestrone-3-O-sulphamate (EMATE), reflected inhibition in other body tissues, activity in WBCs was compared with that in liver and spleen tissue samples from rats. Two hours after an oral dose of EMATE the extent of inhibition of E1-STS detected in WBCs was the same as in the liver. The duration of the inhibition of E1-STS by EMATE, examined over a 1-28 day period in rats, was similar whether monitored in WBCs, liver or spleen. Measurements of E1-STS activity in WBCs were also used to examine the effectiveness of EMATE (0.5 mg/kg) in two male volunteers. E1-STS activity was rapidly inhibited and had only recovered by 27% after 1 month. A marked decrease in the ratio of plasma dehydroepiandrosterone:dehydroepiandrosterone-sulphate (DHA:DHA-S) concentrations was also detected, confirming that EMATE also inhibits DHA-STS activity. The ability to monitor the extent and duration of steroid sulphatase inhibition in WBCs will facilitate the evaluation of this new form of endocrine therapy in women with breast cancer.
Purohit
A
A
Unit of Metabolic Medicine, Imperial College School of Medicine at St. Mary's, London, U.K.
Froome
V A
VA
Wang
D Y
DY
Potter
B V
BV
Reed
M J
MJ
D000818:Animals; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004970:Estrone / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000201:enzymology*; D008099:Liver / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D015203:Reproducibility of Results; D012588:Scintillation Counting / Q000379:methods; D013154:Spleen / Q000201:enzymology; D013429:Sulfatases / Q000037:antagonists & inhibitors* / Q000097:blood*; D014018:Tissue Distribution; D014316:Tritium
D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D014316:Tritium; C088768:estrone-3-O-sulfamate; D004970:Estrone; D013429:Sulfatases; C020121:estrone sulfatase