Suppression of natural antitumour defence mechanisms by phorbol esters

Abstract

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^1,2. Among the various tumour-promoting compounds isolated from croton oil, phorbol-12-myristate-13-acetate (PMA), is the most potent³. 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, DN A synthesis, expression of cell surface glycopeptides, deoxyglucose transport, as well as polyamine, plasminogen activator and ornithine decarboxylase activity are altered^4–6. 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 cells⁴. It is not known whether these agents additionally influence host effector systems involved in antitumour resistance^7–11. 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 phagocytes¹².