This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Laping, N. J. Articles by Walker, C. L. Search for Related Content PubMed PubMed Citation Articles by Laping, N. J. Articles by Walker, C. L.

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.

This article has been cited by other articles:

				T. Fujita, K. Teramoto, Y. Ozaki, J. Hanaoka, N. Tezuka, Y. Itoh, T. Asai, S. Fujino, K. Kontani, and K. Ogasawara Inhibition of Transforming Growth Factor-{beta}-Mediated Immunosuppression in Tumor-Draining Lymph Nodes Augments Antitumor Responses by Various Immunologic Cell Types Cancer Res., June 15, 2009; 69(12): 5142 - 5150. [Abstract] [Full Text] [PDF]