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.