1. ¹Endocrinology and Metabolic Medicine and Sterix Ltd, Faculty of Medicine, Imperial College London, St Mary's Hospital, London W2 1NY, UK
2. ²IPSEN-Biomeasure, 27 Maple Street, Milford, MA, USA
3. ³Medicinal Chemistry and Sterix Ltd, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK

Correspondence: Dr SP Newman, E-mail: simon.newman@imperial.ac.uk

Revised 23 October 2007; Accepted 29 October 2007; Published online 20 November 2007.

Abstract

Therapies for hormone-independent prostate and breast cancer are limited, with the effectiveness of the taxanes compromised by toxicity, lack of oral bioavailability and drug resistance. This study aims to identify and characterise new microtubule disruptors, which may have improved efficacy relative to the taxanes in hormone-independent cancer. 2-Methoxy-3-O-sulphamoyl-17-cyanomethyl-oestra-1,3,5(10)-triene (STX641), 2-methoxy-3-hydroxy-17-cyanomethyl-oestra-1,3,5(10)-triene (STX640) and 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140) were all potent inhibitors of cell proliferation in a panel of prostate and breast cancer cell lines. STX641 and STX640 significantly inhibited tumour growth in the MDA-MB-231 xenograft model. STX641 inhibited both in vitro and in vivo angiogenesis. Despite good in vivo activity, STX641 was not as potent in vivo as STX140. Therefore, STX140 was evaluated in the prostate hormone-independent PC-3 xenograft model. STX140 had superior efficacy to docetaxel, 2-MeOE2 and bevacizumab. In contrast to vinorelbine, no significant toxicity was observed. Furthermore, STX140 could be dosed daily over a 60-day period leading to tumour regression and complete responses, which were maintained after the cessation of dosing. This study demonstrates that STX641 and STX140 have considerable potential for the treatment of hormone-independent breast and prostate cancer. In contrast to the taxanes, STX140 can be dosed orally, with no toxicity being observed even after prolonged daily dosing.