ANTITUMOR EFFECT OF DT-5461, A LIPID-A DERIVATIVE, AGAINST HUMAN TUMOR XENOGRAFTS IS MEDIATED BY INTRATUMORAL PRODUCTION OF TUMOR-NECROSIS-FACTOR AND AFFECTED BY HOST IMMUNOSUPPRESSIVE FACTORS IN NUDE-MICE

We previously reported that DT-5461, a synthetic low-toxic lipid A ana log, inhibits growth of various murine turners through activation of h ost immune systems. In the present study, DT-5461 also exhibited signi ficant antitumor effects against 5 out of 6 human tumor xenografts in nude mice. The antitumor activity was similar to or greater than those of chemotherapeutics. Antitumor effects of DT-5461 significantly corr elated with intratumoral levels of tumor necrosis factor (TNF) induced by the compound (r = 0.701, p < 0.05). In vitro TNF production by DT- 5461-stimulated macrophages was augmented by tumor cells, and the augm entative effect correlated with TNF activity detected in these tumor t issues. Meanwhile, a weaker therapeutic efficacy of DT-5461 was observ ed against certain rumors that caused a significant increase in the le vel of immunosuppressive factors in host blood. These findings support the idea that intratumoral TNF plays a crucial role in the antitumor mechanisms of DT-5461 and suggest that its antitumor action is influen ced by an augmentative effect of tumor cells on TNF production and by blood levels of immunosuppressive factors.