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Tumor-specific efficacy of transforming growth factor-beta RI inhibition in Eker rats Laping NJ; Everitt JI; Frazier KS; Burgert M; Portis MJ; Cadacio C; Gold LI; Walker CLClin Cancer Res 2007[May]; 13 (10): 3087-99PURPOSE: Transforming growth factor beta (TGF-beta), 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-beta signaling could be efficacious for lesions in which TGF-beta 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-beta 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-beta signaling with the ALK5/type I TGF-beta R 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-beta signaling with SB-525334 may be efficacious for mesenchymal tumors, inhibition of this signaling pathway seems to promote the development of epithelial tumors.|Activin Receptors, Type I/*antagonists & inhibitors[MESH]|Animals[MESH]|Apoptosis/drug effects[MESH]|Carcinoma, Renal Cell/*chemically induced/metabolism/pathology[MESH]|Female[MESH]|Imidazoles/*pharmacology/toxicity[MESH]|Kidney Neoplasms/*chemically induced/metabolism/pathology[MESH]|Leiomyoma/*metabolism[MESH]|Mitosis/drug effects[MESH]|Protein Serine-Threonine Kinases[MESH]|Quinoxalines/*pharmacology/toxicity[MESH]|Rats[MESH]|Rats, Inbred Strains[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Transforming Growth Factor beta/*antagonists & inhibitors[MESH]|Signal Transduction/drug effects[MESH]|Transforming Growth Factor beta/antagonists & inhibitors[MESH]|Uterine Neoplasms/*metabolism[MESH] |
