Modulation of radiation induced transformation by combinations of a phorbol diester and a lymphotoxin

The susceptibility of normal Syrian hamster embryo cells to transformation by environmental carcinogens has made possible the determination of a variety of responses as cells proceed to the neoplastic state. Expression of the initiated and promoted stages of irradiation carcinogenesis, for example, can be modified by cell surface alterations. Phytohemagglutin (PHA) or its isolectins decrease 12-O-tetradecanolphorbal-13-acetate (TPA) promoted transformation whereas PHA does not affect carcinogen only induced transformation. In contrast, both initiated and promoted transformation are sensitive to hamster lymphotoxin, a hormone-like, non-antibody lymphocyte glycoprotein. A 48 hr lymphotoxin treatment before or immediately after X-irradiation, or during TPA exposure causes a persistent inhibition independent of when carcinogen was added. A 6 hr lymphotoxin pulse before irradiation and TPA causes a persistent but nonpermanent effect unless followed by the carcinogen treatment; lymphotoxin becomes more potent as the interval between the lymphotoxin pulse and carcinogen insult or TPA addition is reduced. PHA and lymphotoxin affect the biological activity of TPA by diverse mechanisms. PHA may alter either the binding of TPA to a critical cellular receptor for promotion or alter a later step in promotion. Lymphotoxin can prevent the initiation of transformation and modulate carcinogenesis as well at both initiated and promoted stages in the transition to the neoplastic state.