The Pharmaceutical Journal
Vol 270 No 7248 p642
10 May 2003

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Nature Medicine abstract (more)

Novel agent decreases interleukin-2 toxicity

A new class of drug decreases a major toxic effect of a promising anticancer agent and appears to increase its anti-tumour activity.

Recombinant interleukin-2 (IL-2, aldesleukin, Proleukin) is licensed in the United Kingdom for the treatment of metastatic renal cell carcinoma. It is also used in malignant melanoma. However, its toxicity often limits its use to specialist units. A common acute problem is hypotension, often resulting in admission of patients to intensive care, according to the authors of new research. They have found that a new type of drug, a superoxide dismutase mimetic (M40403), may reduce this effect. This agent replicates the catalytic activity of the enzyme superoxide which can cause oxidative damage.

In experiments on mice, the researchers found that the agent reversed IL-2 induced hypotension and allowed the dose of IL-2 to be increased. In one mouse model of cancer the agent induced 50 per cent complete remissions lasting for more than 200 days, compared with survivals of 15 days for untreated mice and 22 days for those treated with IL-2 alone.

The authors of the study, published online by Nature Medicine, explain that the new agent counteracts the production of the superoxide enzyme, thought to be induced by IL-2. The superoxide anion attacks noradrenaline and dopamine by oxidation, leading to loss of their biological functions, including vasoconstriction.

The authors say that an agent that blocks hypotension without affecting the therapeutic mechanism of IL-2 could facilitate IL-2 administration and broaden its clinical use. It would allow higher doses to be used and full courses of therapy to be administered possibly increasing anticancer activity. They propose that, clinically, M40403 should not only inhibit the side effect of hypotension but also potentially increase tumour response rates and survival of patients undergoing IL-2 treatment.

M40403 is being developed by the American company MetaPhore Pharmaceuticals.