Lysosome Labilizers Potentiate the Antitumor Effects of Tumor Necrosis Factor‐α

Enhancement of in vitro cytotoxic activity of tumor necrosis factor‐α (TNF‐α) was observfed in combination with lysosome labilizers, particularly with urokinase‐type plasminogen activator (u‐PA), tissue‐type plasminogen activator (t‐PA) and lipoprotein lipase (LPL). The concentration of TNF‐α resulting in 50% cytotoxicity to L929 cells was only 20–30% of the value for TNF‐α alone, when used in combination with a nontoxic dose of u‐PA, t‐PA or LPL. Furthermore, combined intravenous (i.v.) administration of TNF‐α (3.5 × 10(5) U/mouse) and u‐PA (300 IU/mouse) markedly increased the in vivo antitumor activity of TNF‐α to Meth A tumors transplanted into BALB/c mice; the tumor weight in co‐administered mice was about 40% of that in mice given TNF‐α alone on day 6. The combination therapy of TNF‐α (7.0 × 10(4) U/mouse, i.v.) and u‐PA (300 IU/mouse, i.v.) was also effective for L929 tumors in Crj:CD‐1(1CR)‐nu nude mice compared with the conventional therapy with TNF‐α alone. These results suggest that the combination of TNF‐α and lysosome labilizers is a promising antitumor therapeutic regimen with clinical potential.