新しい生物応答調節剤 : TNF-α産生調節作用を有するフタルイミド誘導体

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Tumor necrosis factor alpha (TNF-α), an important cytokine produced mainly by activated macrophages, plays a critical role in certain physiological immune systems. But it causes severe damage to the host when produced in excess. Therefore, TNF-α can be regarded to possess both favorable and unfavorable effects. These pleiotropic effects indicated that TNF-α production-enhancers in some cases and TNF-α 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 A possible lead compound is thalidomide, which had been used as a hypnotic/sedative agents but was withdrawn from the market because of it's teratogenicity.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-α production, and this effect has been shown to be useful for the treatment of various immunodiseases. Recently, we found that the regulation of TNF-α 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-α production by HL-60 cells, while they inhibit TPA-induced TNF-α production by another human leukemia cell line THP-1,and (II) the compounds inhibit TNF-α production both by HL-60 and THP-1 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-α production is separated. This implies that the target molecule (s) of the two systems are different each other.
公益社団法人日本薬学会の論文
1997-02-25

新しい生物応答調節剤 : TNF-α産生調節作用を有するフタルイミド誘導体

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