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 microM, 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Miles
D
D
Clinical Oncology Unit, Guy's Hospital, London, UK.
Thomsen
L
L
Balkwill
F
F
Thavasu
P
P
Moncada
S
S
D001708:Biopterins / Q000031:analogs & derivatives* / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D001943:Breast Neoplasms / Q000097:blood / Q000628:therapy*; D002277:Carcinoma / Q000097:blood / Q000556:secondary / Q000628:therapy*; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000556:secondary / Q000628:therapy*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007371:Interferon-gamma / Q000097:blood*; D007376:Interleukin-2 / Q000008:administration & dosage*; D007680:Kidney Neoplasms / Q000097:blood / Q000628:therapy*; D008545:Melanoma / Q000097:blood / Q000556:secondary / Q000628:therapy*; D019798:Neopterin; D009569:Nitric Oxide / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D001708:Biopterins; D009569:Nitric Oxide; D019798:Neopterin; D007371:Interferon-gamma