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

Abstract

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.

• Authors: J B Ochoa, B Curti, A B Peitzman, R L Simmons, T R Billiar, R Hoffman, R Rault, D L Longo, W J Urba, A C Ochoa
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 84 Issue 11 Pg. 864-7 (Jun 03 1992) ISSN: 0027-8874 [Print] United States
• PMID: 1375656 (Publication Type: Clinical Trial, Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

• 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, adverse effects, therapeutic use)
• Leukapheresis
• Lymphocyte Activation
• Lymphocyte Transfusion
• Lymphocytes (immunology)
• Male
• Middle Aged
• Neoplasms (blood, immunology, physiopathology, therapy)
• Nitric Oxide (blood)
• Nitric Oxide Synthase
• Nitrogen Oxides (blood)
• Receptors, Antigen, T-Cell (immunology)
• Transplantation, Autologous