4706

Breast cancer in women is of major concern and urgently requires new treatment strategies. High levels of estrogens, found in peripheral tissue, play a significant role in the development of post menopausal breast cancer. There are two main pathways by which estrogens can be synthesised in peripheral tissues, either via the aromatase and/or sulfatase routes. Steroid sulfatase (STS) inhibitors that can decrease or prevent the biosynthesis of estrogens via the sulfatase route may have an important role in the treatment of breast cancer. This work shows the in vivo efficacy in a dual xenograft breast cancer model of two potent STS inhibitors, STX64 and STX213. MCF-7 cells stably expressing STS cDNA (MCF-7[sts]) were generated in-house, with STS activity in these cells being 15 fold higher than in wild type MCF-7 (MCF-7[wt]). Ovariectomised MF-1 female nude mice (nu-/nu-) received subcutaneous (s.c.) injections of estradiol sulfate (E2S) at 0.05mg/0.05ml/mouse 24 hr prior to cell injection. Five million wild type MCF-7[wt] or MCF-7[sts] cells were injected s.c., in Matrigel, into the left and right flanks of the animal respectively. E2S was injected s.c. on alternative days until the end of the study. When tumors reached 100mm3 mice were divided into four groups: vehicle (10% THF:90% PG), STX64 (10mg/kg or 20mg/kg), or STX213 (10mg/kg) treatment. All compounds were given orally for 5 days a week for 49 days. A tumor recovery period of 35 days was then observed during which animals received E2S but no drug treatment. Mice were weighed and tumor measurements taken on a weekly basis. At the end of the study tumors, liver, lung and skin were removed for measurement of STS activity. Both tumors only grew in the presence of the E2S supplement. In the control group tumor volumes increased to 527 ± 87% for MCF-7[wt] and 377 ± 123% for MCF-7[sts] (mean ± SEM) after 49 days compared to week zero. MCF-7[wt] tumor growth was reduced by both STX64 at 20 mg/kg (361 ± 95%) and STX213 (230 ± 123.4%) over the dosing period and subsequent growth was retarded over the recovery period. All treatments were able to significantly inhibit E2S-induced growth of MCF-7[sts] tumors (by 70 to 90% in all treatments), and regrowth of these tumors was also significantly retarded (p < 0.001). Furthermore, all treatments completely inhibited tissue STS activity. No weight loss was observed with any treatment over the entire dosing period. In conclusion, this study indicates that STS inhibitors attenuate breast cancer growth in rodents and therefore offer a potentially novel treatment against breast cancer.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]