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


METHODS
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.


CONCLUSIONS
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.
Laping
Nicholas J
NJ
GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Everitt
Jeffrey I
JI
Frazier
Kendall S
KS
Burgert
Mark
M
Portis
Melisa J
MJ
Cadacio
Caprice
C
Gold
Leslie I
LI
Walker
Cheryl L
CL
D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology* / Q000633:toxicity; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007889:Leiomyoma / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011810:Quinoxalines / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014594:Uterine Neoplasms / Q000378:metabolism*
C521813:6-(2-tert-butyl-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline; D007093:Imidazoles; D011810:Quinoxalines; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat