Regulation of cellular processes by PPARgamma ligands in neuroblastoma cells is modulated by the level of retinoblastoma protein expression.

Neuroblastoma is a childhood cancer, which spontaneously regresses. This has led to a search for agents that mimic this process. We show that both natural and synthetic ligands of PPARgamma (peroxisome-proliferator-activated receptor gamma) inhibit the growth of neuroblastoma cells in vitro. The degree of PPAR activation was attenuated however in the presence of the retinoblastoma protein. Addition of trichostatin A, a histone deacetylase inhibitor, abolished retinoblastoma protein repression of PPAR activity. Moreover, enhanced growth inhibition was observed when neuroblastoma cells were treated with a PPARgamma ligand and a histone deacetylase inhibitor, suggesting a combination therapy to treat neuroblastoma might prove more effective than using either agent alone.

Vascular turnover during carrageenan synovitis in the rat.

Inhibition of angiogenesis has been proposed as a novel therapeutic approach to the treatment of chronic inflammatory diseases such as rheumatoid arthritis. We have assessed carrageenan synovitis in male Wistar rats as a potential model of the increased vascular turnover observed in human synovitis. Intra-articular injection of 100 microl of 2% carrageenan in the right knee on Day 0 was followed by acute joint swelling through Day 3 and persistent macrophage infiltration at Day 28. Endothelial cell proliferation and endothelial cell death each peaked during the acute phase and remained elevated during persistent synovitis. Vascular densities were high in normal synovia, decreased during the acute phase, transiently increased at Day 14, and then returned to control values by Day 28. Lower doses of carrageenan, which stimulated acute joint swelling and macrophage infiltration but not endothelial cell proliferation at Day 3, were not associated with persistent macrophage infiltration at Day 28. Intra-articular injection of substance P or vascular endothelial growth factor, angiogenic factors that are present in normal synovia or are up-regulated during inflammation, respectively, each stimulated endothelial cell expression of proliferating cell nuclear antigen. Increased vascular turnover during acute and persistent phases of synovitis may be regulated by different factors and may serve different roles. The late phase (Day 28) of carrageenan synovitis displays similarities with rheumatoid synovitis, in which endothelial cell turnover is persistently increased despite little overall change in vascular density.