THERAPEUTIC EFFECTS OF A NEW SYNTHETIC LIPID-A ANALOG, ONO-4007, ON RAT HEPATOMA KDH-8 DEPEND ON TUMOR NECROSIS FACTOR-SENSITIVITY OF THE TUMOR-CELLS

ONO-4007 is a new synthetic lipid A derivative with low endotoxic acti vities. ONO-4007 was effective against KDH-8, a tumor necrosis factor (TNF)-sensitive rat hepatoma cell line, but neither effective against KMT-17, a TNF-resistant rat fibrosarcoma cell line, nor SST-2, a TNF-r esistant rat mammary adenocarcinoma cell line. We have established two sublines from KDH-8 to further examine the therapeutic mechanisms of ONO-4007 in vivo: TNF-sensitive KDH-8/YK and TNF-resistant cKDH-8/11. The two sublines equally proliferated in vitro. Multiple systemic i.v. administration of ONO-4007 was performed on days 7, 14 and 21 after t umor implantation. Although treatment with ONO-4007 had no effect on t he growth of cKDH-8/11 in WKAH rats in vivo, 60% of KDH-8/YK-bearing r ats treated with ONO-4007 survived. The administration of ONO-4007 bro ught about significant therapeutic effects on KDH-8/YK-bearing rats bu t not on cKDH-8/11-bearing rats. These results suggest that ONO-4007 i s therapeutically useful for the treatment of TNF-alpha-sensitive tumo rs.