ASSOCIATION BETWEEN BIOSYNTHESIS OF NITRIC-OXIDE AND CHANGES IN IMMUNOLOGICAL AND VASCULAR PARAMETERS IN PATIENTS TREATED WITH INTERLEUKIN-2

Hypotension is a dose-limiting side effect of interleukin-2 (IL-2) therapy. This may be due to increased biosynthesis of the potent vasodilator nitric oxide (NO) induced by cytokines such as tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), which are known to be generated during IL-2 therapy. We describe the relationship between NO biosynthesis and changes in immunological and vascular parameters during IL-2 therapy in 13 patients with metastatic cancer. Plasma concentrations of neopterin and nitrite plus nitrate (NOx) were higher in cancer patients prior to treatment compared with normal subjects (neopterin; 10.8 +/- 1.4 vs. 2.0 +/- 0.4 ng ml(-1), P < 0.001: NOx; 45 +/- 6 vs. 28 +/- 2 mu M, P < 0.005). Pretreatment TNF-alpha and IFN-gamma plasma concentrations were not significantly different in cancer patients from those in controls. During infusion of IL-2 (18 x 10(6) international units m(-2) per day for 5 days) these parameters increased, reaching maximal concentrations at day 3 for IFN-gamma and day 5 for TNF-alpha, neopterin and NOx. The maximal induced NOx correlated with maximal TNF-alpha (r = 0.60, P < 0.04), IFN-gamma, (r = 0.63, P < 0.02) and neopterin (r = 0.66, P < 0.01). As plasma NOx concentrations increased, systolic blood pressure fell, reaching a minimum at day 3 despite a continued rise in NOx concentrations. These changes were accompanied by a continuous increase in pulse rate throughout the infusion period. These findings indicate that induction of NO biosynthesis contributes to hypotension induced during IL-2 therapy. Inhibitors of NO synthase may be useful in limiting toxicity, thus allowing administration of higher and possibly more efficacious doses of this cytokine in the treatment of cancer.