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Research Articles: Therapeutics, Targets, and Development

The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo

¹ Section of Medicine, Institute of Cancer Research, Sutton, United Kingdom; ² Breakthrough Breast Cancer Centre and ³ Department of Academic Biochemistry, Institute of Cancer Research; ⁴ Breast Unit, Royal Marsden Hospital, London, United Kingdom; and ⁵ Oncology Drug Development, Johnson and Johnson PRD, High Wycombe, United Kingdom

Requests for reprints: Lesley-Ann Martin, Breakthrough Breast Cancer Centre, Institute of Cancer Research, Fulham Road, London, SW3 6JB United Kingdom. Phone: 440-207-153-5329; Fax: 440-207-153-5340. E-mail: lesley-ann.martin{at}icr.ac.uk

Abstract

Cross-talk between receptor tyrosine kinases and estrogen receptor is at least partly responsible for the development of acquired resistance to endocrine therapies. Hence, targeting receptor tyrosine kinases and their downstream partners with inhibitors/antagonists may reverse this resistance. Although ras mutations are rare in breast cancer (2%), aberrant function of Ras signal transduction pathways is common. We therefore investigated the efficacy of the farnesyltransferase inhibitor (FTI) R115777 (tipifarnib) in combination with tamoxifen in MCF-7 human breast cancer models both in vitro and in vivo. There was a synergistic antiproliferative interaction between R115777 and 4-hydroxy-tamoxifen in vitro as calculated by median effect analysis. The combination resulted in a significantly greater G₁ arrest than either drug alone and this was associated with marked inhibition of cyclin D1 and induction of the cell cycle inhibitor p27^kip1. Combining R115777 with either tamoxifen or estrogen withdrawal in vivo produced a significantly greater inhibition of tumor growth and lower xenograft cell proliferation than either therapy alone. These results suggest that the combination of this FTI with endocrine therapy may be of therapeutic benefit in the treatment of breast cancer. Enhanced G₁ arrest due to modulation of cell cycle regulatory proteins may be the underlying mechanism for the positive interaction between FTIs and tamoxifen. [Mol Cancer Ther 2007;6(9):2458–67]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: L-A. Martin and J.E. Head contributed equally to this work.

⁶ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 7/31/06; revised 6/14/07; accepted 8/ 1/07.

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