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Tumor-Specific Efficacy of Transforming Growth Factor-ßRI Inhibition in Eker Rats

Authors' Affiliations: ¹ GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania; ² GlaxoSmithKline, Research Triangle Park, North Carolina; ³ University of Texas M.D. Anderson Cancer Center, Science Park, Research Division, Smithville, Texas; and ⁴ New York University School of Medicine, New York, New York

Requests for reprints: Cheryl L. Walker, University of Texas M.D. Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957. Phone: 512-237-9550; Fax: 512-237-2475; E-mail: cwalker{at}wotan.mdacc.tmc.edu.

Purpose: Transforming growth factor ß (TGF-ß), which generally stimulates the growth of mesenchymally derived cells but inhibits the growth of epithelial cells, has been proposed as a possible target for cancer therapy. However, concerns have been raised that whereas inhibition of TGF-ß signaling could be efficacious for lesions in which TGF-ß promotes tumor development and/or progression, systemic pharmacologic blockade of this signaling pathway could also promote the growth of epithelial lesions.

Experimental Design: We examined the effect of a TGF-ß inhibitor on mesenchymal (leiomyoma) and epithelial (renal cell carcinoma) tumors in Eker rats, which are genetically predisposed to develop these tumors with a high frequency.

Results: Blockade of TGF-ß signaling with the ALK5/type I TGF-ßR kinase inhibitor, SB-525334, was efficacious for uterine leiomyoma; significantly decreasing tumor incidence and multiplicity, and reducing the size of these mesenchymal tumors. However, SB-525334 was also mitogenic and antiapoptotic for epithelial cells in the kidney and exacerbated the growth of epithelial lesions present in the kidneys of these animals.

Conclusion: Although pharmacologic inhibition of TGF-ß signaling with SB-525334 may be efficacious for mesenchymal tumors, inhibition of this signaling pathway seems to promote the development of epithelial tumors.