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Research Articles: Therapeutics, Targets, and Development

Suppression of lung cancer tumor growth in a nude mouse model by the Ras inhibitor salirasib (farnesylthiosalicylic acid)

Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

Requests for reprints: Yoel Kloog, Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel. Phone: 972-3-640-9699; Fax: 972-3-640-7643. E-mail: kloog{at}post.tau.ac.il

Abstract

Aberrant Ras pathway functions contribute to the malignant phenotype of lung cancers. Inhibitors of Ras might therefore be considered as potential drugs for lung cancer therapy. Here, we show that the Ras inhibitor farnesylthiosalicylic acid (salirasib) inhibits proliferation of human lung cancer cells harboring a mutated K-ras gene (A549, H23, or HTB54) or overexpressing a growth factor receptor (H1299 or HTB58) and enhances the cytotoxic effect of the chemotherapeutic drug gemcitabine. Salirasib inhibited active K-Ras in A549 cells, reversed their transformed morphology, and inhibited their anchorage-independent growth in vitro. Tumor growth in A549 and HTB58 cell nude mouse models was inhibited by i.p. administration of salirasib. P.o. formulated salirasib also inhibited A549 cell tumor growth. Our results suggest that p.o. salirasib may be considered as a potential treatment for lung cancer therapy. [Mol Cancer Ther 2007;6(6):1765–1773]

Grant support: The Wolfson Foundation.

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: Y. Kloog is the incumbent of The Jack H. Skirball Chair for Applied Neurobiology.

¹ http://www.concordiapharma.com/index.htm

Received 11/14/06; revised 2/19/07; accepted 5/ 2/07.

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