In vitro and in vivo immunosuppressive activity of a novel anthracycline, 13-deoxy, 5-iminodoxorubicin.
We report that the novel anthracycline analog, 13-deoxy, 5-iminodoxorubicin (DIDOX), represents a potentially new class of immunosuppressive agents. DIDOX has been structurally modified from the parent compound, doxorubicin, to remove the carbonyl group at carbon-13 and the quinone moiety at carbon-5 since these structures likely mediate the cardiotoxic side effects of this family of chemotherapeutic drugs. Our studies demonstrate that DIDOX inhibits T cell proliferation and the expression of the T cell activation molecules, CD25 and CD40L. DIDOX also inhibits the production of the pro-inflammatory cytokine, TNF-alpha and IL-2. Studies using animal models demonstrate that DIDOX inhibits the inflammation accompanying contact hypersensitivity reactions and possesses reduced cardiotoxicity compared to doxorubicin. These findings indicate that DIDOX has important immunosuppressive activities that may warrant the development of this new and improved anthracycline for the treatment of T cell-mediated inflammatory diseases.
Olson
Richard D
RD
Boise VA Medical Center, Research Service, Boise, ID 83702, USA.
Headley
Mark B
MB
Hodzic
Alma
A
Walsh
Gerald M
GM
Wingett
Denise G
DG
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003877:Dermatitis, Contact / Q000188:drug therapy / Q000473:pathology; D004139:Dinitrofluorobenzene; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D004452:Echocardiography; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007376:Interleukin-2 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007958:Leukocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D004317:Doxorubicin; D004139:Dinitrofluorobenzene