Mechanisms by which activated normal macrophages destroy syngeneic rat tumour cells in vitro. Cytokinetics, non-involvement of T lymphocytes, and effect of metabolic inhibitors.

Analysis of the kinetics of the interaction between nonimmune activated macrophages and syngeneic tumour cells (induced in inbred DA rats by polyoma virus, dimethylbenzanthracene or methylcholanthrene) has shown that a distinctive series of events can be clearly separated. The earliest consequence of interaction detectable by objective means is a marked decrease in tumour cell proliferation as reflected in the reduction of the capacity of tumour cells to incorporate DNA precursors such as [H]thymidine. By 3—4 hours, the cytostatic effect is strongly marked, and is essentially established after 12 hours of interaction. Shrinkage, agglutination and decrease in the number of tumour cells as examples of the morphological consequences of cytostatic target cell damage accomplished by activated macrophages are rarely perceptible before 10–12 hours although the tumour cells have completely disappeared after 24–48 hours. Under the experimental conditions employed, occasional tumour cells escaped interaction with activated macrophages. The fact that such recovery of targets was fully reversed by adding further activated macrophages indicates that tumour cell revival reflects a decrease in macrophage effector functions during prolonged incubation. The possibility that some tumour cells might be resistant to macrophage effects thus seems excluded. Activated macrophages from normal and from congenitally athymic nude mice are equally effective in reducing tumour cell proliferation. Thus T lymphocytes and/or their soluble mediators are not essential for the macrophage function under investigation. Pretreatment of activated macrophages with an extensive array of metabolic inhibitors and agents known to affect distinct cellular functions yields much data but does not yet permit a simple comprehensive interpretation. However, the findings are compatible with the thesis that macrophage activation is accompanied by the or enhanced synthesis of the cytostatic principle. Once possessed of this mechanism, other basic functional capacities of macrophages, such as membrane activity, movement or endocytosis are no longer essential for the mediation of the cytostatic effects.