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Research Articles: Therapeutics, Targets, and Development

Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer

Departments of ¹ Surgery and ² Pulmonary Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; ³ Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; and ⁴ Vascular Biology Program, Department of Surgery, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts

Requests for reprints: Fiemu E. Nwariaku, Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9156. Phone: 214-648-9968; Fax: 214-648-4784. E-mail: Fiemu.nwariaku{at}utsouthwestern.edu

Abstract

Anaplastic thyroid carcinoma is an aggressive form of cancer with no treatment. Angiogenesis inhibitors, such as TNP-470, a synthetic derivative of fumagillin, have been shown to reduce tumor size and increase survival in heterotopic animal models of thyroid cancer. Our goals were to determine the effect of TNP-470 on anaplastic thyroid cancer using an orthotopic murine model, to identify the molecular pathways of TNP-470 actions on endothelial cells, and to determine the non-endothelial tumor effects of TNP-470. We injected human anaplastic thyroid carcinoma cells (DRO'90) into the thyroid glands of nude mice. Mice received TNP-470 (30 mg/kg) s.c. for 6 weeks. TNP-470 prolonged survival and reduced liver metastases. TNP-470 had direct cytotoxic effects on anaplastic thyroid carcinoma cells in vitro and in vivo. Paradoxically, TNP-470 increased vascular endothelial growth factor secretion from tumor cells in vitro and in vivo. However, there was no associated increase in tumor microvessel density. In endothelial cells, TNP-470 prevented vascular endothelial growth factor–induced endothelial permeability, intercellular gap formation, and ruffle formation by preventing Rac1 activation. [Mol Cancer Ther 2007;6(4):1329–37]

Grant support: American Heart Association grant 0535019N (D. Nahari), Robert Wood Johnson Foundation/Harold Amos Medical Faculty Development Program (F.E. Nwariaku), and NIH grants RO1 GM067674-01A1 (F.E. Nwariaku), R01-HL61897 (L. Terada), and R01-HL67256 (L. Terada).

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.

Received 9/ 8/06; revised 11/16/06; accepted 2/ 8/07.