Effectiveness and toxicity of protracted nitric oxide synthesis inhibition during IL-2 treatment of mice.
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 N omega monomethyl-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 microM/mouse/day), and normal mice (from 1 to 0.5 microM/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.
Samlowski
W E
WE
University of Utah Cancer Immunotherapy Program, University of Utah School of Medicine, Salt Lake City, USA.
Yim
C Y
CY
McGregor
J R
JR
Kwon
O D
OD
Gonzales
S
S
Hibbs
J B
JB
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D007167:Immunotherapy; D066298:In Vitro Techniques; D007260:Infusion Pumps; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology / Q000633:toxicity; D012513:Sarcoma, Experimental / Q000276:immunology / Q000628:therapy; D019323:omega-N-Methylarginine / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
D004791:Enzyme Inhibitors; D007376:Interleukin-2; D011994:Recombinant Proteins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase