Efficacy of three potent steroid sulfatase inhibitors: pre-clinical investigations for their use in the treatment of hormone-dependent breast cancer.
Estrogenic steroids, such as estradiol, are known to play a crucial role in the development and growth of hormone-dependent breast cancer. Steroid sulfatase (STS) inhibitors that can prevent the biosynthesis of these steroids via the sulfatase pathway offer therapeutic potential. We show here the in vivo profile, including the efficacy in a xenograft breast cancer model and pharmacokinetics, of three potent STS inhibitors. MCF-7 cells stably over-expressing STS cDNA (MCF-7STS) were generated. Ovariectomised, MF-1, female nude mice receiving subcutaneous injections of estradiol sulfate (E2S) and bearing MCF-7STS xenografts, were orally treated with the STS inhibitors STX64, STX213, and STX1938. Treatment was administered once weekly at a dose of 1 mg/kg for 35 days during which animals received E2S thrice weekly. Mice were weighed and tumor measurements taken weekly. Furthermore, the pharmacokinetics for STX213 was determined in rats. STX213 and STX1938 exhibited potent STS inhibition in vivo. However, STX1938 demonstrated a greater duration of activity. In vehicle treated nude mice receiving E2S, tumor volumes increased by 260% after 35 days compared to day zero. STX64 (1 mg/kg) failed to reduce tumor growth when given once weekly. STX213 and STX1938 (once weekly, 1 mg/kg) significantly inhibited (P < 0.05) tumor growth over this same time period. These compounds completely inhibited liver and tumor STS activity and significantly reduced the levels of plasma E2. This study indicates that the STS inhibitor, STX213, exhibits excellent efficacy and pharmacokinetics and therefore offers a potentially novel treatment for hormone-dependent breast cancer.
Foster
Paul A
PA
Department of Endocrinology and Metabolic Medicine and Sterix Ltd, Imperial College Faculty of Medicine, St Mary's Hospital, London, W2 1NY, UK. paul.foster@imperial.ac.uk
Chander
Surinder K
SK
Parsons
Michael F C
MF
Newman
Simon P
SP
Woo
L W Lawrence
LW
Potter
Barry V L
BV
Reed
Michael J
MJ
Purohit
Atul
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001378:Azasteroids / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013451:Sulfonic Acids / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001378:Azasteroids; D004791:Enzyme Inhibitors; C515227:STX 213; D013451:Sulfonic Acids; C520511:irosustat; D043266:Steryl-Sulfatase