PMID: 9539777May 16, 1998Paper

The tetravalent guanylhydrazone CNI-1493 blocks the toxic effects of interleukin-2 without diminishing antitumor efficacy

Proceedings of the National Academy of Sciences of the United States of America
M M KemenyK J Tracey

Abstract

The use of interleukin 2 (IL-2) as an antineoplastic agent has been limited by the serious toxicities that accompany the doses necessary for a tumor response. Elevation of nitric oxide (NO) and tumor necrosis factor (TNF) both have been implicated in IL-2 toxicities. CNI-1493, a tetravalent guanylhydrazone, is an inhibitor of macrophage activation including the synthesis of TNF and other cytokines. Doses of CNI-1493 as low as 1 mg/kg/day conferred complete protection against fatal toxicity of IL-2 with IL-2 doses tenfold higher than the safely tolerated level in Sprague-Dawley rats. Moreover, typical pathologic changes in the lungs, kidneys, and the liver caused by IL-2 infusion were blocked by cotreatment with CNI-1493. When animals bearing established hepatomas were given IL-2 and CNI-1493 combination therapy, 10 of 10 hepatomas regressed from 1 cm3 to <1 mm3. Intracytoplasmic TNF levels were increased in normal tissues from IL-2 treated animals, and treatment with CNI-1493 maintained TNF at control levels. The degree of apoptosis measured by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining of tumors following IL-2 therapy was not reduced compared with IL-2 cotreated with CNI-1493. In contr...Continue Reading

References

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Citations

Aug 2, 2001·Clinics in Dermatology·D ReintgenM Atkins
Feb 24, 2001·Autonomic Neuroscience : Basic & Clinical·L V BorovikovaK J Tracey
Mar 29, 2006·Journal of Burn Care & Research : Official Publication of the American Burn Association·Adam J SingerMarcia Simon
Oct 29, 2015·Mediators of Inflammation·Ting LiuHeping Yang
Oct 16, 2004·Immunobiology·Elisabeth ZinserAlexander Steinkasserer
Dec 11, 2007·Journal of Leukocyte Biology·Stacey L Oke, Kevin J Tracey
May 20, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jin WangHenri R Ford
Jul 31, 2018·Journal of Oncology·Marijke De CouckYori Gidron

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