DECREASED MACROPHAGE-MEDIATED CYTOTOXICITY IN MAMMARY-TUMOR-BEARING MICE IS RELATED TO ALTERATION OF NITRIC-OXIDE PRODUCTION AND OR RELEASE/

Peritoneal-exudate macrophages (PEM) from mammary-tumor-bearing mice h ave impaired cytotoxic activity against syngeneic and allogeneic tumor targets. The ability of PEM from normal and tumor-bearing mice to bin d tumor targets was found to be similar in the presence or the absence of surrogate receptors, which enhanced the binding but not the killin g of tumor targets by PEM from tumor-bearing mice, suggesting that oth er mechanisms are involved in their impaired cytolytic activity. Solub le and membrane-bound TNF-alpha as well as H2O2, were found in higher amounts in PEM from tumor bearers upon stimulation with LPS, as compar ed with PEM from normal mice. However, tumor-bearers' macrophages disp layed decreased capacity to produce and/or release nitric oxide, which could be reversed by the addition of increasing levels of IFN-gamma. These results indicate that the lack of macrophage cytotoxicity in mam mary-tumor-bearing mice is related to impaired production and/or relea se of NO by these effector cells, possibly aggravated by the insuffici ent IFN-gamma production previously reported in these animals. Moreove r, mammary-tumor progression results in dis-regulation of synthesis of macrophage-mediators, with over-production of molecules to which mamm ary-tumor cells are insensitive and deficient production of NO, the cr ucial molecule to which these cells appear to be highly sensitive. (C) 1995 Wiley-Liss, Inc.