Strategies to reduce side effects of interleukin-2: evaluation of the antihypotensive agent NG-monomethyl-L-arginine

Abstract

Purpose: The clinical utility of high-dose intravenous recombinant interleukin (IL)-2 therapy is limited by severe toxicity including hypotension, fever, chills, pulmonary edema, and oliguria Hypotension has been previously shown to result from excessive vascular relaxation due to overproduction of the endogenous vasodilator nitric oxide. Nitric oxide production can be decreased by administration of the competitive enzyme inhibitor NG-monomethyl-L-arginine (NMA). A clinical trial to investigate the dose-dependent effects of NMA on blood pressure was undertaken in patients with metastatic renal cell carcinoma.

Patients and methods: Patients with metastatic renal cell carcinoma receiving a 5-day continuous infusion of IL-2 (18 million IU/m2/d) who developed hypotension were treated with increasing doses of NMA, ranging from 3 to 36 mg/kg.

Results: Twenty-three patients received a total of 61 courses of IL-2; 18 of these patients developed hypotension and received NMA. Antihypotensive activity was observed at all dose levels, and the duration of the effect varied directly with the dose of NMA. At the higher dose levels tested (12 to 36 mg/kg), increased pulmonary vascular resistance and decreased cardiac output were observed. Patients experiencing a significant decrease in cardiac output received dobutamine (2.5 to 10 microg/kg/min). Pulmonary capillary wedge pressure was unaffected by administration of NMA. One patient treated at 24 mg/kg (bolus) experienced a major motor seizure, but no neurologic disorders were observed in other patients treated with NMA doses of 24 to 36 mg/kg. No other adverse events involving hepatic, renal, or hematologic systems were attributed to NMA. Three patients received NMA by an initial bolus followed by a continuous infusion. Similar antihypotensive effects were noted, and these patients were able to complete a full 5-day course of IL-2.

Conclusion: The antihypotensive effects of NMA appear to be optimal at a dose of 24 mg/kg, with maintenance doses of 8 mg/kg every 4 to 6 hours. At this dose level, blood pressure was restored, and IL-2-associated vasodilatation was fully reversed. Coincident with the reversal of hypotension, the state of high cardiac output was also reversed by NMA administration. These results suggest that NMA may be effective for alleviating the hypotensive effects of high-dose IL-2 therapy in cancer patients.