A nonpeptidyl mimic of superoxide dismutase, M40403, inhibits dose-limiting hypotension associated with interleukin-2 and increases its antitumor effects.
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.
Samlowski
Wolfram E
WE
Melanoma Program, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, Utah 84112, USA.
Petersen
Ryan
R
Cuzzocrea
Salvatore
S
Macarthur
Heather
H
Burton
Damali
D
McGregor
John R
JR
Salvemini
Daniela
D
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D002395:Catecholamines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007022:Hypotension / Q000139:chemically induced* / Q000517:prevention & control; D007376:Interleukin-2 / Q000627:therapeutic use* / Q000633:toxicity; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000473:pathology; D007694:Killer Cells, Natural / Q000378:metabolism; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008345:Manganese; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism*; D015996:Survival Rate
D000970:Antineoplastic Agents; D002395:Catecholamines; D007376:Interleukin-2; D009942:Organometallic Compounds; C121876:imisopasem manganese; D008345:Manganese; D013482:Superoxide Dismutase