Suppression of natural antitumour defence mechanisms by phorbol esters

Chemical carcinogenesis in certain tissues occurs in at least two stages: initiation, producing irreversible tissue alterations, and promotion (by agents, themselves non-carcinogenic), enhancing the outgrowth of transformed cells. Among the various tumour-promoting compounds isolated from croton oil, phorbol-12-myristate-13-acetate (PMA), is the most potent. Cell culture studies have shown that the phorbol diesters and structurally related substances induce a variety of dramatic changes in diverse eukaryotic cells. Spreading, differentiation, metabolism, DNA synthesis, expression of cell surface glycopeptides, deoxyglucose transport, as well as polyamine, plasminogen activator and ornithine decarboxylase activity are altered. These findings indicate that tumour promoters potentiate expression of the transformed phenotype in cells already malignantly transformed and also induce reversible manifestations of the transformed phenotype in normal cells. It is not known whether these agents additionally influence host effector systems involved in antitumour resistance. The present study is concerned with the effects of PMA on spontaneous in vitro cytotoxicity by macrophages and/or natural killer (NK) cells, and on the resistance to rat fibrosarcoma in vivo considered to depend on these normal effectors, in particular on mononuclear phagocytes.