© 1990 by Oxford University Press
Journal of the National Cancer Institute, Vol. 82, No. 9, 772-776,
May 2, 1990
© 1990 Oxford University Press
Endothelial Cell Production of Nitrogen Oxides in Response to Interferon 
in Combination With Tumor Necrosis Factor, Interleukin-1, or Endotoxin
Department of Medical Oncology, Genitourinary Section,The University of Texas M. D. Anderson Cancer Center Houston, TX
Department of Tumor Biology,The University of Texas M. D. Anderson Cancer Center Houston, TX
*Correspondence to: Robert G. Kilboum, Ph.D., Department of Medical Oncology, Genitourinary Section, The University of Texas M. D. Anderson Cancer Center, Box 13, 1515 Holcombe Blvd., Houston, TX 77030.
Clinical studies using biological response modifiers in cancer therapy have shown that the major dose-limiting toxic effects are hypotension and diffuse microvascular leakage. The cause and pathophysiology of this hypotension remains unknown. Previous experiments have demonstrated that a number of cell types, including endothelial cells, neu-trophils, and macrophages, can secrete a potent hypotensive agent—endothelium-derived relaxing factor, which has recently been identified as nitric oxide. In this study, we tested interferon 
, tumor necrosis factor, interleukin-1, in-terleukin-2, muramyl dipeptide, and endotoxin for their effects on production of nitrogen oxides by endothelial cells. Interferon y, in combination with tumor necrosis factor, interleukin-1 (IL-1), or endotoxin, induced murine brain endothelial cells to secrete nitrites (20–45 µM within 48 hr), which are breakdown products of nitric oxide. Nitrite production was blocked by incubation of endotheliai cells in medium without L-arginine, a substrate for nitric-oxide synthase. Accumulation of nitrites was also inhibited by addition of NG-monomethyl-L-arginine (l-NMMA), which acts as a competitive inhibitor of this enzyme. The inhibitory effects of l-NMMA were reversed by addition of excess L-arginine. These results suggest (a) that endothelial cells produce nitric oxide in response to immunomod-ulators and (b) that endothelial cell-derived nitric oxide plays a role in the development of hypotension in patients treated with tumor necrosis factor or interleukins. Furthermore, administration of substrate analogues such as l-NMMA may favorably alter the toxicity associated with these immunomodulators and result in a higher maximum tolerated dose, with subsequent improvement in the antitumor activity. J Natl Cancer Inst 82: 772–brief-report776, 1990]
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