A NEW SYNTHETIC LIPID-A ANALOG, ONO-4007, STIMULATES THE PRODUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA IN TUMOR-TISSUES, RESULTING IN THE REJECTION OF TRANSPLANTED RAT HEPATOMA-CELLS

ONO-4007 is a new synthetic lipid A derivative with low endotoxic acti vities. We have examined the therapeutic effects of ONO-4007 on rat he patocellular carcinoma KDH-8 cells, rat fibrosarcoma KMT-17 cells and rat mammary adenocarcinoma SST-2 cells in vivo. Multiple systemic i.v. administration of ONO-4007 was performed on days 7, 14 and 21 after t umor implantation of KDH-8 and SST-2 cells, and on days 5, 10 and 15 a fter tumor implantation of KMT-17 cells. ONO-4007 showed significant t herapeutic effects on KDH-8 cells; by the administration of ONO-4007 ( 2.5 mg/kg) 70% of rats were cured and by the administration of ONO-400 7 (5 mg/kg) 50% of rats were cured. Furthermore, the ONO-4007 treatmen t prolonged the mean survival time of KDH-8-bearing rats. However, ONO -4007 had no effect on KMT-17 and SST-2 cells, and it had no direct ef fect on the growth of KDH-8 cells in vivo. Albeit the stimulation with ONO-4007 induced mRNA expressions of interleukin (IL)-1 alpha, IL-6 a nd tumor necrosis factor (TNF)-alpha, those of IL-2, IL-4, IL-10 and i nterferon (IFN)-gamma were not induced. Using a bioassay, we found tha t the production of TNF-alpha in the tumor tissues was induced by ONO- 4007 in a dose-dependent manner, KDH-8 cells were sensitive to human n atural TNF-alpha in vitro. However, KMT-17 and SST-2 cells were resist ant against TNF-alpha in vitro. These results suggest that ONO-4007 is therapeutically useful for the treatment of TNF-alpha-sensitive tumor s.