To the editor

I read with great interest the report by Samlowski et al. entitled, “A nonpeptidyl mimic of superoxide dismutase, M40403, inhibits dose-limiting hypotension associated with interleukin-2 and increases its antitumor effects.”1 These findings are potentially important in reducing the capillary leakage associated with interleukin-2 therapy, and other disorders of capillary leakage including acute respiratory distress syndrome. However, the antitumor effect of M40403 in vivo may be due in part to inhibition of reactive oxygen in tumor cells themselves. We have previously shown that genes that generate reactive oxygen can cause transformation associated with increased angiogenesis, and that reduction of reactive oxygen in these transformed tumor cells leads to decreased angiogenesis2. Certain tumors, namely those associated with high levels of mitogen-associated protein kinase activation and loss of the tumor-suppressor gene CDKN2A, are also associated with high levels of reactive oxygen3,4,5. Melanoma is one such tumor, and introduction of manganese superoxide dismutase (MnSOD) into melanoma cells reduces tumorigenicity in vivo6.

Samlowski et al. show that at a single-dose level, M40403 has no effect on tumor growth in vivo (see figure on p. 753 of the June issue). Two possibilities come to mind to explain why introduction of MnSOD into melanoma cells has a direct antitumor effect6, whereas M40403 did not at the particular dose examined in this study. First, there is the matter of dosage. Higher doses of M40403 may have direct antitumor activity in vivo. Second, high levels of reactive oxygen are associated with resistance to interferon-α- and interferon-β-mediated cell killing7, and perhaps to interleukin-12-mediated cell death. The reduction of reactive oxygen in the tumor cells themselves with M40403 may sensitize the cells to immune-mediated destruction. The use of systemic MnSOD mimics without systemic toxicity is encouraging; these agents may act through several mechanisms, including reducing vascular leakage, inhibiting the production of angiogenic factors and stimulating apoptosis through inhibition of reactive oxygen and NF-κB signaling.

See Reply to “Role of manganese superoxide dismutase in cancer” by Salvemini et al.