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Association between biosynthesis of nitric oxide and changes in immunological and vascular parameters in patients treated with interleukin‐2
Author(s) -
MILES D.,
THOMSEN L.,
BALKWILL F.,
THAVASU P.,
MONCADA S.
Publication year - 1994
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/j.1365-2362.1994.tb01087.x
Subject(s) - neopterin , nitric oxide , medicine , endocrinology , tumor necrosis factor alpha , nitrite , blood pressure , vasodilation , chemistry , nitrate , organic chemistry
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‐ α (TNF‐ α ) and interferon‐ γ (IFN‐ γ ), 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 (NO x ) 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: NO x ; 45±6 vs. 28±2 μ M, P <0·005). Pretreatment TNF‐ α and IFN‐ γ plasma concentrations were not significantly different in cancer patients from those in controls. During infusion of IL‐2 (18 times 10 6 international units m ‐2 per day for 5 days) these parameters increased, reaching maximal concentrations at day 3 for IFN‐ γ and day 5 for TNF‐ α , neopterin and NO x . The maximal induced NO x correlated with maximal TNF‐ α (r = 0·60, P <0·04), IFN‐ γ (r = 0·63, P <0·02) and neopterin (r = 0·66, P <0·01). As plasma NO x concentrations increased, systolic blood pressure fell, reaching a minimum at day 3 despite a continued rise in NO x 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.