Increased circulating nitrogen oxides after human tumor immunotherapy: Correlation with toxic hemodynamic changes

Background: Toxicity to interleukin-2 (IL-2) tumor immunotherapy is manifested principally by the vascular leak syndrome, hypotension, and a hyper-dynamic response with low systemic vascular resistance. Nitric oxide(·N = O), a recently discovered biological mediator of vascular smooth muscle relaxation, is produced in increased amounts by numerous cell types exposed to a number of inflammatory cytokines. Purpose: Our purpose was to determine if there is an increased production of ·N = O in patients receiving IL-2 tumor immunotherapy, and, if so, whether increases in ·N = O production correlate with hemodynamic instability. Methods: Twelve patients undergoing immunotherapy trials with IL-2 and anti-CD3 monoclonal antibody-activated lymphocytes (T-AK cells) were studied. Plasma levels of nitrate (NO₃-), the stable end metabolic product of ·N = O synthesis, were measured before and at the end of IL-2 treatment cycles. Results: We observed a ninefold increase in plasma levels of NO_3- in patients after 7 days of treatment (P<.0001). A significant decrease in both systolic and diastolic blood pressures was observed in all patients (P<.001). Conclusions: We propose that mediated induction of ·N = O synthase enzyme leads to progressive increases in ·N = O production which, in turn, produces clinically significant hypotension. Implications: Since ·N = O synthesis can be competitively inhibited by L-arginine analogues, a possible pharmacologic modulation of N = O production could potentially contribute to better management of toxic side effects seen in IL-2 cancer therapies. [J Natl Cancer Inst 84: 864-867, 1992]