Inhibition of platelet-derived growth factor-mediated signal transduction and tumor growth by N-[4-(trifluoromethyl)-phenyl]5-methylisoxazole-4-carboxamide.

摘要: Many reports have cited coexpression of platelet-derived growth factor (PDGF) and its receptors by tumor cells or supporting growth, suggesting both autocrine paracrine mechanisms for PDGF-mediated growth. We found that a small organic molecule, N-[4-(trifluoromethyl)phenyl] 5-methylisoxazole-4-carboxamide (SU101, leflunomide), inhibited signaling events, including receptor tyrosine phosphorylation, DNA synthesis, cell cycle progression, proliferation. SU101 PDGF-stimulated phosphorylation PDGF (PDGFR) beta in C6 (rat glioma) NIH3T3 engineered to overexpress human PDGFRbeta (3T3-PDGFRbeta). blocked PDGF- epidermal (EGF)-stimulated synthesis. Previously, this compound was shown inhibit pyrimidine biosynthesis interfering with the enzymatic activity dihydroorotate dehydrogenase. In current study, EGF-stimulated synthesis restored addition saturating quantities uridine, whereas PDGF-induced not, demonstrated some selectivity PDGFR pathway independent biosynthesis. Selectivity further ability block entry into S phase cycle, without affecting progression cells. assays, selectively PDGFRbeta-expressing lines more efficiently than it PDGFRbeta-negative lines. s.c., i.p., intracerebral panel from glioma, ovarian, prostate origin. contrast, failed vitro s.c. A431 KB cells, which express EGF but not PDGFRbeta. also D1B L1210 (murine leukemia) syngeneic immunocompetent mice, causing adverse effects on immune response animals. an i.p. model prevented induced long-term survivors animals implanted 7TD1 B-cell hybridoma) Because detected most vivo SU101, these data suggest is effective inhibitor PDGF-driven vivo.