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STX140 Is Efficacious In vitro and In vivo in Taxane-Resistant Breast Carcinoma Cells

Authors' Affiliations: ¹ Endocrinology and Metabolic Medicine and Sterix, Ltd., Faculty of Medicine, Imperial College London, St Mary's Hospital, London, United Kingdom; ² XenTech, Evry, France; ³ IPSEN Research Laboratories, Institut Henri Beaufour, Les Ulis Cedex, France; and ⁴ Medicinal Chemistry and Sterix, Ltd., Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom

Requests for reprints: Simon P. Newman, Endocrinology and Metabolic Medicine, Faculty of Medicine, Imperial College London, St Mary's Hospital, London W2 1NY, United Kingdom. Phone: 44-207-886-1210; Fax: 44-207-886-1790; E-mail: simon.newman{at}imperial.ac.uk.

Purpose: The aim of these studies was to characterize the action of STX140 in a P-glycoprotein–overexpressing tumor cell line both in vitro and in vivo. In addition, its efficacy was determined against xenografts derived from patients who failed docetaxel therapy.

Experimental Design: The effects of STX140, Taxol, and 2-methoxyestradiol (2-MeOE2) on cell proliferation, cell cycle, and apoptosis were assessed in vitro in drug-resistant cells (MCF-7_DOX) and the parental cell line (MCF-7_WT). Mice bearing an MCF-7_DOX tumor on one flank and an MCF-7_WT tumor on the other flank were used to assess the in vivo efficacy. Furthermore, the responses to STX140 of three xenografts, derived from drug-resistant patients, were assessed.

Results: In this study, STX140 caused cell cycle arrest, cyclin B1 induction, and subsequent apoptosis of both MCF-7_DOX and MCF-7_WT cells. Taxol and 2-MeOE2 were only active in the MCF-7_WT parental cell line. Although both STX140 and Taxol inhibited the growth of xenografts derived from MCF-7_WT cells, only STX140 inhibited the growth of tumors derived from MCF-7_DOX cells. 2-MeOE2 was ineffective at the dose tested against both tumor types. Two out of the three newly derived docetaxel-resistant xenografts, including a metastatic triple-negative tumor, responded to STX140 but not to docetaxel treatment.

Conclusions: STX140 shows excellent efficacy in both MCF-7_WT and MCF-7_DOX breast cancer xenograft models, in contrast to Taxol and 2-MeOE2. The clinical potential of STX140 was further highlighted by the efficacy seen in xenografts recently derived from patients who had failed on taxane therapy.