ANTITUMOR EFFECT OF DT-5461A, A SYNTHETIC LOW-TOXICITY LIPID-A ANALOG, INVOLVES ENDOGENOUS TUMOR-NECROSIS-FACTOR INDUCTION SUBSEQUENT TO MACROPHAGE ACTIVATION

We previously showed that the synthetic lipid A derivative DT 5461a ex hibited significant antitumor effects against various murine solid tum ors, probably via activation of host immune systems. To clarify the pa rticipation of the macrophage-stimulating effect of DT-5461a in the an titumor mechanisms, we studied the ability of this compound to induce cytostatic macrophages and TNF production in murine systems. Cytostati c macrophages were induced by treatment with DT-5461a either in vitro or in vivo. DT-5461a also induced TNF production by resident peritonea l macrophages or spleen cells obtained From untreated mice. When splee n cells prepared from DT-5461a-treated mice were re-stimulated in vitr o with DT-5461a no TNF was produced by cells obtained at 1 day after t he treatment. This may be due to transient refractoriness of macrophag es to the compound, since the response to re-stimulation with DT-5461a recovered in cells obtained at 3 or 5 days after treatment. Moreover, while the serum TNF production and antitumor effects by DT-5461a decr eased on daily administration, they were elicited by intermittent admi nistration at intervals of 3 days or more. This suggests that the anti tumor effects of DT-5461a depend on the TNF-producing activity of macr ophages. These results indicate that DT-5461a possesses significant ma crophage-stimulating activity, and that macrophages so activated media te the DT-5461a-induced augmentation of host response against solid tu mors.