Discodermolide--a new, marine-derived immunosuppressive compound. I. In vitro studies.
The in vitro immunosuppressive properties of a novel, marine-derived compound, discodermolide, are reported here. Discodermolide suppressed the proliferative responses of splenocytes in the murine two-way mixed lymphocyte reaction (MLR) and concanavalin A stimulated cultures, with IC50 values of 0.24 microM and 0.19 microM, respectively. There was no evidence of cytotoxicity for murine splenocytes at concentrations of discodermolide as high as 1.26 microM. Similarly, discodermolide suppressed the proliferative responses of human peripheral blood leukocytes (PBL) in the two-way MLR, and Con A and phytohemagglutinin mitogenesis. The IC50 values were 5.65 microM, 28.02 microM, and 30.12 microM for the MLR, Con A, and PHA mitogenic responses, respectively. There was no evidence of cytotoxicity toward human PBL at discodermolide concentrations as high as 80.64 microM. Discodermolide was equally effective, compared with cyclosporine, in suppressing the PMA-ionomycin induced proliferation of purified, murine T cells, with IC50 values of 9.0 nM and 14.0 nM for discodermolide and CsA, respectively. The production of IL-2 by PMA-ionomycin stimulated T cells was not inhibited by discodermolide; however, the percentage of IL-2 receptor-bearing cells as measured by immunofluorescence with 7D4 antibody, specific for the 55-kDa chain (p55) comprising the murine IL-2 receptor, was reduced. The expression of a similar chain comprising the human IL-2 receptor (Tac antigen, p55) by PHA or Con-A-stimulated PBL was similarly suppressed by discodermolide. The precise mechanism of action of discodermolide remains to be elucidated.
Longley
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Division of Biomedical Marine Research, Harbor Branch Oceanographic Institution, Inc., Fort Pierce, Florida 34946.
Caddigan
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Harmody
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Gunasekera
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Gunasekera
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D000473:Alkanes; D000818:Animals; D002219:Carbamates; D002478:Cells, Cultured; D003208:Concanavalin A / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011753:Pyrones; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000473:Alkanes; D002219:Carbamates; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007783:Lactones; D011753:Pyrones; D015375:Receptors, Interleukin-2; D003208:Concanavalin A; D015759:Ionomycin; C071229:discodermolide; D013755:Tetradecanoylphorbol Acetate