Clinical Cancer Research 2007-05-15

Tumor-specific efficacy of transforming growth factor-beta RI inhibition in Eker rats.

Nicholas J Laping, Jeffrey I Everitt, Kendall S Frazier, Mark Burgert, Melisa J Portis, Caprice Cadacio, Leslie I Gold, Cheryl L Walker

Index: Clin. Cancer Res. 13 , 3087-3099, (2007)

Full Text: HTML

Abstract

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.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.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.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.

Related Compounds

  • SB525334

Related Articles:

Mesenchymal activin-A overcomes defective human trisomy 21 trophoblast fusion.

2011-12-01

[Endocrinology 152 , 5017-28, (2011)]

Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-beta type I receptor kinase in puromycin-induced nephritis.

2005-06-01

[J. Pharmacol. Exp. Ther. 313 , 943-951, (2005)]

Activin-Like Kinase 5 (ALK5) Mediates Abnormal Proliferation of Vascular Smooth Muscle Cells from Patients with Familial Pulmonary Arterial Hypertension and Is Involved in the Progression of Experimental Pulmonary Arterial Hypertension Induced by Monocrotaline

2009-01-01

[Am. J. Pathol. 174(2) , 380-9, (2009)]

Inhibition of activin receptor-like kinase 5 attenuates bleomycin-induced pulmonary fibrosis.

2007-08-01

[Exp. Mol. Pathol. 83 , 39-46, (2007)]

More Articles...