TY - JOUR
T1 - Effectiveness and toxicity of protracted nitric oxide synthesis inhibition during il-2 treatment of mice
AU - Samlowski, Wolfram E.
AU - Yim, Chang Yeol
AU - McGregor, John R.
AU - Kwon, Oh Deog
AU - Gonzales, Shane
AU - Hibbs, John B.
PY - 1995/10
Y1 - 1995/10
N2 - The current study was designed to characterize nitric oxide (NO-) synthesis during interleukin-2 (IL-2) treatment of mice, and to determine whether NO- mediated IL-2-induced “vascular leak.‘’ We developed a technique for chronic subcutaneous infusion of the NO- synthase inhibitor Nωmonomethyl-L-arginine (MLA) via osmotic minipump to aid in further study of these processes. After IL-2 administration to C3H/HeN mice (180,000 IU i.p. b.i.d. for 5 days), NO- synthesis increased two-to-three fold, peaking on days 5–8. Administration of MLA reduced NO- synthesis in both IL-2-treated mice (from 2.7 to 1 μM/mouse/day), and normal mice (from 1 to 0.5 μM/mouse/day). This agent decreased IL-2-induced radiolabeled albumin accumulation in the liver after i.p. IL-2 administration (p < 0.02). MLA infusions resulted in minimal systemic toxicity in mice, as reflected by complete blood counts or serum chemistries. MLA also did not impair lymphokine-activated killer cell induction in vitro or in vivo, or alter IL-2-induced tumor responses in a 3-day pulmonary metastasis model. These experiments demonstrated that NO- is a mediator involved in the genesis of vascular permeability induced by IL-2 treatment. Studies designed to further evaluate the toxicity and usefulness of MLA infusions to modify this IL-2 induced toxicity appear to be warranted.
AB - The current study was designed to characterize nitric oxide (NO-) synthesis during interleukin-2 (IL-2) treatment of mice, and to determine whether NO- mediated IL-2-induced “vascular leak.‘’ We developed a technique for chronic subcutaneous infusion of the NO- synthase inhibitor Nωmonomethyl-L-arginine (MLA) via osmotic minipump to aid in further study of these processes. After IL-2 administration to C3H/HeN mice (180,000 IU i.p. b.i.d. for 5 days), NO- synthesis increased two-to-three fold, peaking on days 5–8. Administration of MLA reduced NO- synthesis in both IL-2-treated mice (from 2.7 to 1 μM/mouse/day), and normal mice (from 1 to 0.5 μM/mouse/day). This agent decreased IL-2-induced radiolabeled albumin accumulation in the liver after i.p. IL-2 administration (p < 0.02). MLA infusions resulted in minimal systemic toxicity in mice, as reflected by complete blood counts or serum chemistries. MLA also did not impair lymphokine-activated killer cell induction in vitro or in vivo, or alter IL-2-induced tumor responses in a 3-day pulmonary metastasis model. These experiments demonstrated that NO- is a mediator involved in the genesis of vascular permeability induced by IL-2 treatment. Studies designed to further evaluate the toxicity and usefulness of MLA infusions to modify this IL-2 induced toxicity appear to be warranted.
KW - Interleukin-2
KW - Lymphokineactivated killer cells
KW - Monomethyl-L-arginine
KW - Nitric Oxide
KW - Vascular leak syndrome
UR - http://www.scopus.com/inward/record.url?scp=0029559131&partnerID=8YFLogxK
U2 - 10.1097/00002371-199510000-00004
DO - 10.1097/00002371-199510000-00004
M3 - Article
C2 - 8770772
AN - SCOPUS:0029559131
SN - 1524-9557
VL - 18
SP - 166
EP - 178
JO - Journal of Immunotherapy
JF - Journal of Immunotherapy
IS - 3
ER -
