1. ¹Department of Endocrinology and Metabolic Medicine and Sterix Ltd., Imperial College London, St Mary's Hospital, London W2 1NY, UK
2. ²Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Bath BA2 7AY, UK

Correspondence: Dr JM Day, Department of Endocrinology and Metabolic Medicine and Sterix Ltd., Imperial College London, St. Mary's Hospital, 2nd Floor, Mint Wing, Winsland Street, London W2 1NY, UK. E-mail: joanna.day@imperial.ac.uk

Received 7 October 2008; Revised 8 December 2008; Accepted 10 December 2008; Published online 20 January 2009.

Abstract

The anti-proliferative and anti-angiogenic properties of the endogenous oestrogen metabolite, 2-methoxyoestradiol (2-MeOE2), are enhanced in a series of sulphamoylated derivatives of 2-MeOE2. To investigate possible mechanisms of resistance to these compounds, a cell line, A2780.140, eightfold less sensitive to the 3,17-O,O-bis-sulphamoylated derivative, STX140, was derived from the A2780 ovarian cancer cell line by dose escalation. Other cell lines tested did not develop STX140 resistance. RT–PCR and immunoblot analysis demonstrated that breast cancer resistance protein (BCRP) expression is dramatically increased in A2780.140 cells. The cells are cross-resistant to the most structurally similar bis-sulphamates, and to BCRP substrates, mitoxantrone and doxorubicin; but they remain sensitive to taxol, an MDR1 substrate, and to all other sulphamates tested. Sensitivity can be restored using a BCRP inhibitor, and this pattern of resistance is also seen in a BCRP-expressing MCF-7-derived cell line, MCF-7.MR. In mice bearing wild-type (wt) and BCRP-expressing tumours on either flank, both STX140 and mitoxantrone inhibited the growth of the MCF-7wt xenografts, but only STX140 inhibited growth of the MCF-7.MR tumours. In conclusion, STX140, a promising orally bioavailable anti-cancer agent in pre-clinical development, is highly efficacious in BCRP-expressing xenografts. This is despite an increase in BCRP expression in A2780 cells in vitro after chronic dosing with STX140.