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

J Natl Cancer Inst. 1992 Jun 3;84(11):864-7. doi: 10.1093/jnci/84.11.864.


Background: Toxicity to interleukin-2 (IL-2) tumor immunotherapy is manifested principally by the vascular leak syndrome, hypotension, and a hyperdynamic 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 NO3- in patients after 7 days of treatment (P less than .0001). A significant decrease in both systolic and diastolic blood pressures was observed in all patients (P less than .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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Oxidoreductases / biosynthesis
  • Antibodies, Monoclonal / therapeutic use
  • Antigens, CD / immunology
  • Antigens, Differentiation, T-Lymphocyte / immunology*
  • Biomarkers / blood
  • Blood Pressure / drug effects*
  • CD3 Complex
  • Enzyme Induction
  • Female
  • Free Radicals / blood
  • Humans
  • Hypotension / etiology
  • Immunotherapy*
  • Infusions, Intravenous
  • Injections, Intravenous
  • Interleukin-2 / administration & dosage
  • Interleukin-2 / adverse effects*
  • Interleukin-2 / therapeutic use
  • Leukapheresis
  • Lymphocyte Activation
  • Lymphocyte Transfusion
  • Lymphocytes / immunology*
  • Male
  • Middle Aged
  • Neoplasms / blood
  • Neoplasms / immunology
  • Neoplasms / physiopathology
  • Neoplasms / therapy*
  • Nitric Oxide / blood*
  • Nitric Oxide Synthase
  • Nitrogen Oxides / blood*
  • Receptors, Antigen, T-Cell / immunology*
  • Transplantation, Autologous


  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Biomarkers
  • CD3 Complex
  • Free Radicals
  • Interleukin-2
  • Nitrogen Oxides
  • Receptors, Antigen, T-Cell
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Amino Acid Oxidoreductases