THE TETRAVALENT GUANYLHYDRAZONE CNI-1493 BLOCKS THE TOXIC EFFECTS OF INTERLEUKIN-2 WITHOUT DIMINISHING ANTITUMOR EFFICACY

The use of interleukin 2 (IL-2) as an antineoplastic agent has been li mited by the serious toxicities that accompany the doses necessary for a tumor response. Elevation of nitric oxide (NO) and tumor necrosis f actor (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 toxi city 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 hepato mas were given IL-2 and CNI-1493 combination therapy, 10 of 10 hepatom as regressed from 1 cm(3) to <1 mm(3). Intracytoplasmic TNF levels wer e increased in normal tissues from IL-2 treated animals, and treatment with CNI-1493 maintained TNF at control levels. The degree of apoptos is measured by terminal deoxynucleotidyltransferase-mediated dUTP-biot in nick end labeling staining of tumors following IL-2 therapy was not reduced compared with IL-2 cotreated with CNI-1493. In contrast, apop tosis in the liver and lung parenchyma following IL-2 therapy was bloc ked completely by cotreatment with CNI-1493. Taken together, these dat a showed that low and infrequent doses of CNI-1493 markedly protected animals from IL-2 systemic toxicities whereas not affecting tumor resp onse to IL-2 therapy. With the protection afforded by CNI-1493 treatme nt, IL-2 therapy dose levels could be increased to provide significant antitumor effects in animals with established hepatomas.