Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite.

作者：Tetsuro Fujita, Ken‐ichiro Inoue, Satoshi Yamamoto, Takeshi Ikumoto, Shigeo Sasaki, RYOUSUKE TOYAMA, Kenji Chiba, Yukio Hoshino, Takeki Okumoto · 发表于：The Journal of Antibiotics · 年份：1994 · DOI：10.7164/antibiotics.47.208 · 被引用次数：543 · 研究领域：Macrophage Migration Inhibitory Factor、Bioactive Compounds and Antitumor Agents、Cancer therapeutics and mechanisms

A potent immunosuppressive activity was found in the culture broth of the fungus Isaria sinclairii (ATCC 24400).The metabolite, ISP-I ((2JS,3^,4^)-(j&)-2-amino-3,4-dihydroxy-2-hydroxymethyl-14oxoeicos-6-enoic acid, myriocin = thermozymocidin) suppressed the proliferation of lymphocytes in mouse allogeneic mixed lymphocyte reaction, but had no effect on the growth of humantumor cell lines.It also suppressed the appearance of plaque-forming cells in response to sheep red blood cells and the generation of allo-reactive cytotoxic T lymphocytes in mice after intraperitoneal or oral administration.The metabolite was 10-to 100-fold more potent than cyclosporin A as an immunosuppressiveagent of the immuneresponse in vitro and in vivo, and appears to be a candidate for clinical application as a powerful immunosuppressant.The success of humanorgan transplantations is dependent upon the use of potent immunosuppressive drugs.Cyclosporin A (CsA)2), a fungal cyclic peptide, is one such drug with powerful immunosuppressive properties in experimental and clinical organ transplantations.Recently, FK-5063f4), a novel macrolide from Streptomyces tsukubaensis, was found to be 10-to 100-fold more potent than CsA as an immunosuppressantand is currently under clinical trial.These two compoundsappear to have very similar immunosuppressive properties, but higher doses of both compounds induce renal dysfunction and other side effects.Therefore, improved drugs for the prevention of graft rejection with...