Systemic administration of a synthetic lipid A derivative, DT-5461a, reduces tumor blood flow through endogenous TNF production in hepatic cancer model of VX2 carcinoma in rabbits.

Intravenous administration of DT-5461a, synthetic low-toxicity lipid A derivative, significantly inhibited the growth of VX2 tumor transplanted in the liver of rabbits. DT-5461a induced high levels of TNF activity in tumor tissue from 30 to 60 min after the administration, while no TNF activity was detected in the adjacent nontumorous liver tissue. Simultaneous measurement of microcirculatory blood flow in both tumorous and nontumorous regions in the liver by laser doppler velocimetory revealed that intravenous administration of DT-5461a caused a significant blood flow reduction in tumor region, but not in nontumorous counterparts. Tumor blood flow was significantly reduced by 40 to 60% at 30 to 90 min after the DT-5461a administration as compared with preadministration value. In contrast, local administration of human recombinant TNF alpha through the hepatic artery induced blood flow reduction not only in tumor region but also in nontumorous liver tissue. These results suggest that systemic administration of DT-5461a induced selective tumor microcirculatory blood flow reduction via local endogenous TNF production.