INTRATUMORAL PRODUCTION OF TUMOR-NECROSIS-FACTOR AUGMENTED BY ENDOGENOUS INTERFERONS RESULTS IN POTENT ANTITUMOR EFFECTS OF DT-5461, A SYNTHETIC LIPID-A ANALOG

We previously reported that DT-5461 exhibits potent antitumor effects on various murine syngeneic tumors, probably via activation of host im mune systems. Of the various systemic administration routes, intraveno us (i.v.) administration gave the best antitumor effects. When the tot al dose was fixed, multiple and intermittent applications resulted in greater therapeutic efficacy than single and daily applications, respe ctively. The therapeutically effective applications of DT-5461 induced endogenous tumor necrosis factor (TNF) activity in serum and tumor ti ssue. The TNF activity peaked at 1-2 h after the administration. Altho ugh TNF activity in the serum declined to an undetectable level by 4 h , intratumoral TNF activity persisted even at 16 h. TNF-alpha messenge r RNA (mRNA) was clearly expressed in the tumor tissues as early as 0. 5 h after the DT-5461 administration. DT-5461 also caused increases in interferon activity in tumor-bearing mice. In vivo treatment with ant i-interferon-alpha/beta serum or anti-interferon-gamma serum, as well as with anti-TNF-alpha serum, significantly reduced the antitumor effe ct of DT-5461. DT-5461-induced endogenous TNF production was also inhi bited by treatment with either of these anti-interferon antisera alone . These results suggest that intermittent i.v. administration is optim al for cancer treatment with DT-5461, and that the optimal application of DT-5461 causes a long-lasting production of intratumoral TNF-alpha that may play a crucial role in the antitumor mechanisms of this comp ound. Furthermore, endogenous interferons induced by DT-5461 are invol ved in the antitumor mechanisms of this compound, probably by regulati ng the intratumoral TNF induction.