A nonpeptidyl mimic of superoxide dismutase, M40403, inhibits dose-limiting hypotension associated with interleukin-2 and increases its antitumor effects.
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Samlowski WE, Petersen R, Cuzzocrea S, Macarthur H, Burton D, McGregor JR, Salvemini D
A nonpeptidyl mimic of superoxide dismutase, M40403, inhibits dose-limiting hypotension associated with interleukin-2 and increases its antitumor effects.
Nat Med. 2003 Jun;9(6):750-5. Epub 2003 May 5.
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- 12730689 [ View in PubMed]
- Abstract
Interleukin-2 (IL-2) is used to treat metastatic renal cell carcinoma and malignant melanoma, but its use is limited by the severe hypotension it produces. We have shown here that M40403, a superoxide dismutase (SOD) mimetic, blocked IL-2-induced hypotension and allowed the dose of IL-2 to be increased in mice. The reversal of IL-2-mediated hypotension was associated with an increase in plasma catecholamines. In addition, M40403 increased lymphokine-activated killer (LAK) cell cytotoxicity in vitro and in vivo, through inhibition of macrophage superoxide production. Treatment of methylcholanthrene-induced (Meth A) ascites tumors with IL-2 and > or =3 mg per kg body weight M40403 induced 50% complete remissions lasting for more than 200 d, which was longer than those of untreated mice (15-d median survival) or mice treated with IL-2 alone (22-d median). Growth of subcutaneous implants of RENCA renal carcinoma was also inhibited by the combination of IL-2 and M40403. These results established that M40403 prevented IL-2 from causing dose-limiting hypotension, while enhancing its anticancer activity.
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