Novel biological response modifiers: Phthalimides with TNF-alpha production regulating activity

Tumor necrosis factor alpha (TNF-alpha), an important cytokine produced mainly by activated macrophages, plays a critical role in certain physiological immune systems. Rut it causes severe damage to the host when produced in excess. Therefore, TNF-alpha can be regarded to possess both favorable and unfavorable effects. These pleiotropic effects indicated that TNF-alpha production-enhancers in some cases and TNF-alpha production-inhibitors in other cases would be useful as biological response modifiers (BRMs) under various circumstances. A possible lead compound is thalidomide, which had been used as a hypnotic/sedative agents but was withdrawn from the market because of it's teratogenicity. Thalidomide is a specific inhibitor of TNF-alpha production, and this effect has been shown to be useful for the treatment of various immunodiseases. Recently, we found that the regulation of TNF-alpha production by thalidomide and related phthalimides was both inducer-specific and cell-type-specific, i.e., (I) the compounds enhance 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced TNF-alpha production by HL-60 cells, while they inhibit TPA-induced TNF-alpha production by another human leukemia cell line THP-I, and (II) the compounds inhibit TNF-alpha production both by HL-60 and THP-I cells when the cells are stimulated with okadaic acid. We also found that in a optically active phthalimide analogues of thalidomide the inducer specific bi-directional regulation of TNF-alpha production is separated. This implies that the target molecule(s) of the two systems are different each other.