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Chapter category: Ischemia-Reperfusion
Evaluation of a Superoxide Dismutase Mimetic As an Adjunct to Interleukin 2 Based Cancer Therapy
Chapter authors:
Wolfram E. Samlowski, Ryan Petersen, John R. McGregor, Muralidher Kondapaneni and Daniela Salvemini
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Interleukin-2 (IL-2) is currently used to treat patients with metastatic renal cell carcinoma
and malignant melanoma. Clinical use of IL-2 is limited by severe side effects, particularly
hypotension. Because of such dose-limiting side effects, the full period of IL-2 dosing is
frequently curtailed. Our study demonstrates that M40403, a synthetic superoxide dismutase
mimetic (SODm), which catalytically remove superoxide anions, reversed IL-2 induced hypotension
in a murine model. M40403 allowed the dose of IL-2 to be increased significantly.
Reversal of hypotension was attributed to inhibition of superoxide-driven deactivation of endogenously
released catecholamines. Furthermore, M40403 increased IL-2 induced lymphocyte
cytotoxicity both in vitro and in vivo. This appeared to relate to effects on
macrophage-produced superoxide. Enhanced cytotoxic lymphocyte activation by IL-2 plus
M40403 appeared to correlate with enhancement of IL-2 induced tumor responses against
Meth A spindle cell ascites tumor. The combination of IL-2 and M40403 induced 50% complete
remissions, lasting >120 days compared to untreated mice (15 day median survival), or
mice treated with IL-2 (21 day median). M40403 also increased the response of subcutaneous
RENCA renal carcinoma implants to IL-2 treatment. These results establish that M40403
inhibits the dose limiting hypotension due to IL-2 through a novel mechanism while enhancing
anti-cancer activity.
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