Immunomodulatory Properties of the Novel Anthracycline Analog, GPX-150: Implications for the Treatment of Chronic Inflammatory Disease

Publication Date

9-2005

Type of Culminating Activity

Thesis

Degree Title

Master of Science in Biology

Department

Biology

Supervisory Committee Chair

Denise Wingett

Supervisory Committee Member

Henry Charlier

Supervisory Committee Member

Julia Oxford

Abstract

In this study we investigate the immunomodulatory properties of 5-imino-13-deoxydoxorubicin (GPX-150), a novel anthracycline analog with expected reduced cardiotoxicity. This cumulative dose-dependent and potentially fatal cardiotoxicity has prevented the use of anthracyclines outside the treatment of life-threatening diseases. Anthracyclines have commonly been used in the treatment of a variety of cancers due to their potent anti-mitogenic properties. GPX-150 has been structurally modified from the parent compound, doxorubicin, to replace the carbonyl at carbon-13 with a methylene oxygen and the quinone at carbon-5 with an imino group. These structures are believed to mediate anthracycline cardiotoxic side effects, and the indicated modifications have been shown to prevent cardiotoxicity. In doing so it is now reasonable to evaluate a potential role for the drug in the treatment of non life-threatening diseases. The potent anti-mitogenic properties of anthracyclines may make them particularly suited to the treatment of chronic inflammatory diseases, such as psoriasis, where T cell proliferation is a critical component of disease pathogenesis. Our studies demonstrate that GPX-150 dose-dependently inhibits T cell proliferation and the expression of T cell activation molecules including membrane-bound CD25 and CD40L as well as the soluble form of the CD40L protein. Additional studies show that GPX-150 inhibits the production of the proinflammatory cytokine, TNF-α, yet increases both IL-12 and IFN-γ indicating that this drug may selectively modulate T cell function. Studies using animal models demonstrate that GPX-150 inhibits the inflammation accompanying contact hypersensitivity reactions and possesses negligible cardiotoxicity compared to doxorubicin. These findings indicate the GPX-150 possesses important immunosuppressive activities on T cells that may warrant the development of this new and improved anthracycline for the treatment of inflammatory disease.

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