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 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.


OBJECTIVE
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.


CONCLUSIONS
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.
Ochoa
J B
JB
Department of Surgery, University of Pittsburgh, PA 15261.
Curti
B
B
Peitzman
A B
AB
Simmons
R L
RL
Billiar
T R
TR
Hoffman
R
R
Rault
R
R
Longo
D L
DL
Urba
W J
WJ
Ochoa
A C
AC
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects*; D017252:CD3 Complex; D004790:Enzyme Induction; D005260:Female; D005609:Free Radicals / Q000097:blood; D006801:Humans; D007022:Hypotension / Q000209:etiology; D007167:Immunotherapy; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D007937:Leukapheresis; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D009569:Nitric Oxide / Q000097:blood*; D019001:Nitric Oxide Synthase; D009589:Nitrogen Oxides / Q000097:blood*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D014182:Transplantation, Autologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015415:Biomarkers; D017252:CD3 Complex; D005609:Free Radicals; D007376:Interleukin-2; D009589:Nitrogen Oxides; D011948:Receptors, Antigen, T-Cell; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases