Inducer-specific bidirectional regulation by thalidomide and phenylphthalimides of tumor necrosis factor-α production

Regulation by thalidomide [N(α)-phthalimidoglutarimide] of tumor necrosis factor (TNF)-α production was found to be inducer-specific. Thalidomide enhances TNF-α production by human leukemia HL-60 cells induced with 12-O-tetradecanoylphorbol 13-acetate (TPA), while it inhibits TNF-α production induced with okadaic acid (OA) in the same cell line. Some phthalimide analogs, including PP-33 [2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione] and its 4,5,6,7-tetrafluoro derivative (FPP-33), also showed such an inducer-specific bidirectional TNF-α production-regulating activity. The structure-activity relationships of the compounds tested are similar, but not identical, in the TPA-stimulated HL-60 and OA-stimulated HL-60 assay systems.