A nonpeptidyl mimic of superoxide dismutase, M40403, inhinbts dose-limiting hypotension associated with

interleukin-2 and increases its antitumor effects.

Speaker: 徐毅玲

Commentator : 蕭璦莉老師

Time: 10/1/2003 13:00-14:00

Place: Room 601

Abstract:

    Interleukin 2 (IL-2), a T-cell growth factor, is central in the activation of cell-mediated immune response.  Low concentrations of IL-2 are necessary for the

activation and clonal expansion of cytolytic lymphocytes.  IL-2 is also the only immunotherapy approved by the FDA for the treatment of melanoma and renal

cancer.  But one of the limitations for broader application of IL-2-based cancer treatment is its toxicity, including severe hypotension.  The development of an agent

that blocks hypotension without affecting the therapeutic effect of IL-2 is thus important.  According to previous findings, the pattern of hypotension and

myocardial depression after IL-2 therapy seems similar to septic shock. Overproduction of superoxide is essential in the pathogenesis of organ dysfunction

during septic shock.  Superoxide is able to deactivate endogeneous catecholamines which are critical to maintaining blood pressure.  As a result, the author of this article tried to use M40403, a superoxide dismutase (SOD) mimetic to block IL-2-induced hypotension in mice.  They found out that M40403 not only blocks IL-2-induced hypotension, but also increases lymphokine-activated killer (LAK) cell cytotoxicity in vitro and in vivo by inhibition of macrophage superoxide production.  Most impressively, in the two mouse tumor model not very

sensitive to IL-2 (RENCA and MethA), IL-2 and M40403 led to a much greater antitumor effect.  The author thus have identified a promising new agent, M40403, that  reverses the hypotension associated with IL-2 treatment and allowes IL-2 dose to be increased in animal models.  Thus, it gives us a new way to better treat renal cancer, melanoma and other tumor in the future.

References:

1. Salvemini, D. et al. Synzyme: potent non-peptidic agents against superoxide-driven tissue ingury. Science 286, 304-306 (1999)

2. Macarthur, H. et al. Inactivation of catecholamines by superoxide gives new insight into the pathogenesis of septic shock. Proc. Natl. Acad. Sci 97, 9753-9758 (2000)