Steroid pretreatment reduces interleukin-2 toxicity in sheep.

Abstract

Recombinant interleukin-2 (rIL-2) has shown promise in the treatment of patients with advanced cancer. However, toxicity of this therapy remains a major problem with its use in some patients. In this study we examined whether steroids could reduce the adverse cardiopulmonary effects of rIL-2. Seven sheep were surgically prepared with vascular catheters and lung lymph fistulas. Each sheep received either a single dose of rIL-2 (100 micrograms/kg) or rIL-2 plus methylprednisolone (30 mg/kg) followed by the reverse treatment 1 week later. Lung lymph flow increased markedly after rIL-2 with a peak QL of 140% +/- 30% (above baseline). Steroid pretreatment significantly reduced this lymph flow increase with peak lung lymph flow being only 40% +/- 16% (p less than 0.004). The lymph/plasma protein ratio tended to increase after rIL-2, but these changes were not statistically significant. After rIL-2, cardiac output, heart rate, core temperature, and mean pulmonary artery pressure increased (p less than 0.05), whereas systemic vascular resistance and arterial PO2 decreased (p less than 0.05). These changes did not occur with steroid pretreatment. The results of this study demonstrate that steroids reduced the adverse cardiopulmonary effects of rIL-2. We believe that rIL-2 induces activation of arachidonic acid metabolism, which leads to the production of multiple inflammatory mediators that cause increased microvascular permeability and the adverse cardiopulmonary effects of rIL-2.