Lysosome labilizers potentiate the antitumor effects of tumor necrosis factor-alpha.
Enhancement of in vitro cytotoxic activity of tumor necrosis factor-alpha (TNF-alpha) was observed 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-alpha resulting in 50% cytotoxicity to L929 cells was only 20-30% of the value for TNF-alpha alone, when used in combination with a nontoxic dose of u-PA, t-PA or LPL. Furthermore, combined intravenous (i.v.) administration of TNF-alpha (3.5 x 10(5) U/mouse) and u-PA (300 IU/mouse) markedly increased the in vivo antitumor activity of TNF-alpha 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-alpha alone on day 6. The combination therapy of TNF-alpha (7.0 x 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-alpha alone. These results suggest that the combination of TNF-alpha and lysosome labilizers is a promising antitumor therapeutic regimen with clinical potential.
Biotechnology Research Laboratories, Teijin Limited, Tokyo.
T
T
Masegi
A
A
Kato
K
K
Kitai
M
M
Fukuoka
K
K
Soma
Y
Y
Ichikawa
S
S
Nakamura
N
N
Watanabe
Y
Y
Niitsu
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D004357:Drug Synergism; D008071:Lipoprotein Lipase / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology
D014409:Tumor Necrosis Factor-alpha; D008071:Lipoprotein Lipase; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator