Intratumoral production of tumor necrosis factor augmented by endogenous interferons results in potent antitumor effects of DT-5461, a synthetic lipid A analog.

Abstract

We previously reported that DT-5461 exhibits potent antitumor effects on various murine syngeneic tumors, probably via activation of host immune systems. Of the various systemic administration routes, intravenous (i.v.) administration gave the best antitumor effects. When the total dose was fixed, multiple and intermittent applications resulted in greater therapeutic efficacy than single and daily applications, respectively. The therapeutically effective applications of DT-5461 induced endogenous tumor necrosis factor (TNF) activity in serum and tumor tissue. The TNF activity peaked at 1-2 h after the administration. Although TNF activity in the serum declined to an undetectable level by 4 h, intratumoral TNF activity persisted even at 16 h. TNF-alpha messenger 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 anti-interferon-alpha/beta serum or anti-interferon-gamma serum, as well as with anti-TNF-alpha serum, significantly reduced the antitumor effect of DT-5461. DT-5461-induced endogenous TNF production was also inhibited by treatment with either of these anti-interferon antisera alone. These results suggest that intermittent i.v. administration is optimal 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 compound. Furthermore, endogenous interferons induced by DT-5461 are involved in the antitumor mechanisms of this compound, probably by regulating the intratumoral TNF induction.