Inhibition of nitric oxide synthesis does not improve interleukin-2-mediated antitumor effects in vivo.
Nitric oxide (NO) decreases cytotoxicity and proliferation of cytotoxic lymphocytes (CTLs) in vitro. Both can be prevented by inhibitors of the NO synthase (NOS). To elucidate whether inhibition of the IL-2-induced NOS could boost efficacy of IL-2-stimulated CTLs in vivo, we assessed lung metastases in mice injected with IL-2, the NOS inhibitor aminoguanidine (AG), their combination and the diluent. No improvement was observed for IL-2 + AG compared to IL-2 while NO production was normalized. Since NO causes one of the two major side effects of IL-2 treatment, hypotension, we further studied whether capillary leak could be attributed to NO, too. While IL-2-inducible NO was reduced to control levels by AG, pulmonary edema was unaffected. Thus a decrease in NO does not improve antitumor effects of IL-2-stimulated CTLs nor does it attenuate IL-2-associated capillary leak.
Leder
G H
GH
Department of Surgery, University of Pittsburgh School of Medicine, USA.
Oppenheim
M
M
Rosenstein
M
M
Shah
N
N
Hoffman
R
R
Lotze
M T
MT
Beger
H G
HG
D000818:Animals; D002199:Capillary Permeability; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011654:Pulmonary Edema / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D006146:Guanidines; D007376:Interleukin-2; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C004479:pimagedine