m-40403 and Melanoma

Despite increasing use of "targeted therapy," interleukin-2 (IL-2) is unique, because this cytokine can induce long-term remissions in 5% to 7% of patients with metastatic melanoma and renal cancer. Clinical use of IL-2 is limited by severe toxicities, such as hypotension and vascular leak syndrome (VLS). Nitric oxide seems to be involved in the pathogenesis of these toxicities. On the basis of previous studies, we hypothesized that the endothelial nitric oxide synthase (eNOS) is the major source of nitric oxide. Mice with a knockout of the eNOS isoenzyme were treated with IL-2 (800,000 IU twice daily for 5 d). Blood pressure and vascular leak were measured. Inhibitors of superoxide, nitric oxide, and soluble guanylate cyclase were used to probe the mechanism. These experiments showed that IL-2 treatment increased eNOS messenger ribonucleic acid expression and nitric oxide metabolite excretion in eNOS knockout mice. Unlike normal and inducible nitric oxide synthase knockout mice, eNOS knockout mice proved resistant to IL-2-induced hypotension and vascular leak. Although hypotension seems to be mediated by superoxide or peroxynitrite, vascular leak seemed to be mediated by nitric oxide. Inhibition of guanylate cyclase and cyclic guanylate monophosphate formation during IL-2 treatment using methylene blue (MB)-inhibited vascular leak. MB treatment did not interfere with IL-2-induced antitumor mechanisms. Our experiments established that eNOS is a key mediator of IL-2-induced VLS and hypotension. A clinical trial of MB infusion during IL-2 therapy is currently being planned.

Topics: Animals; Blood Pressure; Capillary Leak Syndrome; Carcinoma, Renal Cell; Cyclic GMP; Enzyme Inhibitors; Guanylate Cyclase; Humans; Hypotension; Interleukin-2; Manganese; Melanoma; Methylene Blue; Mice; Mice, Inbred Strains; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type III; omega-N-Methylarginine; Organometallic Compounds; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Soluble Guanylyl Cyclase; Superoxides

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.

Topics: Animals; Antineoplastic Agents; Catecholamines; Dose-Response Relationship, Drug; Female; Humans; Hypotension; Interleukin-2; Kidney Neoplasms; Killer Cells, Natural; Lymphocyte Activation; Macrophages; Manganese; Melanoma; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Molecular Mimicry; Molecular Structure; Organometallic Compounds; Superoxide Dismutase; Survival Rate

Topics: Animals; Antineoplastic Agents; Humans; Interleukin-2; Kidney Neoplasms; Manganese; Melanoma; Mice; Organometallic Compounds; Superoxides; Survival Rate

Topics: Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Interleukin-2; Manganese; Melanoma; Molecular Mimicry; Organometallic Compounds; Reactive Oxygen Species; Superoxide Dismutase