Lg. Corral et al., SELECTION OF NOVEL ANALOGS OF THALIDOMIDE WITH ENHANCED TUMOR-NECROSIS-FACTOR-ALPHA INHIBITORY ACTIVITY, Molecular medicine, 2(4), 1996, pp. 506-515
Citations number
21
Categorie Soggetti
Biology,"Medicine, Research & Experimental","Cell Biology
Background: Tumor necrosis factor or (TNF alpha) is thought to mediate
both protective and detrimental manifestations of the inflammatory re
sponse. Recently, thalidomide (alpha-N-phthalimidoglutarimide) was sho
wn to partially inhibit monocyte TNF alpha production (by 50-70%) both
in vivo and in vitro. More efficient inhibition of TNF alpha may, how
ever, be necessary to rescue the host from more acute and extensive to
xicities of TNF alpha-mediated inflammation. Materials and Methods: Th
ree structural analogues of thalidomide were selected for study based
on increased activity against TNF alpha production. The parent drug an
d the analogs were tested in vitro in human peripheral blood mononucle
ar cell cultures for their effects on lipopolysaccharide (LPS) induced
cytokine protein and mRNA production using ELISAs and Northern blot h
ybridization. The in vitro effects of the drugs were then confirmed in
vivo in a mouse model of LPS induced lethality. Results: The new comp
ounds (two esters and one amide) showed increased inhibition of TNF al
pha production by LPS-stimulated human monocytes, relative to the pare
nt drug thalidomide. The analogs and the parent drug enhanced the prod
uction of interleukin 10 (IL-10), but had little effect on IL-6 and IL
-1 beta protein and mRNA production. When tested in vivo, the amide an
alog protected 80% of LPS-treated mice against death from endotoxin in
duced shock. Conclusions: Analogs of thalidomide designed to better in
hibit TNF alpha production in vitro have correspondingly greater effic
acy in vivo. These finding may have therapeutic implication for the tr
eatment of human diseases characterized by acute and extensive TNF alp
ha production such as tuberculous meningitis or toxic shock.