TYROSINE KINASE INHIBITOR AS A NOVEL SIGNAL-TRANSDUCTION AND ANTIPROLIFERATIVE AGENT - PROSTATE-CANCER

In prostate cancer cells, the binding of peptide growth factors to spe cific receptors increases tyrosine kinases (TK) activity to regulate c ell proliferation, cell differentiation, and signaling processes. To d etermine whether inhibition of receptor TK activity inhibits tumor gro wth, we studied the effects of a tyrosine kinase inhibitor, RG-13022 ( tyrphostin), on cultured human prostate cancer cells. RG-13022 signifi cantly inhibited TGF alpha-induced phosphorylation of EGF receptor (EG FR). This compound inhibited TGF alpha-stimulated [H-3]thymidine incor poration in a dose-dependent manner with IC50 being 30 mu M. Clonogeni city in soft agar was reduced in the presence of RG-13022. Inhibitory effects were also observed in androgen-positive LNCaP cells and androg en-negative PC3 cells. RG-13022 not only inhibited TGF alpha-induced g rowth but also growth stimulated by epidermal growth factor (EGF), aci dic fibroblast growth factor (aFGF) and serum. In addition, RG-13022 a lso blocked androgen-stimulated cell proliferation, suggesting that fu nctioning TK pathways are required for androgen-induced growth. This n ovel synthetic inhibitor may be useful in providing a new strategy for future therapeutic intervention for prostate cancer.