Antitumor effect of DT-5461, a lipid A derivative, against human tumor xenografts is mediated by intratumoral production of tumor necrosis factor and affected by host immunosuppressive factors in nude mice.
We previously reported that DT-5461, a synthetic low-toxic lipid A analog, inhibits growth of various murine tumors through activation of host immune systems. In the present study, DT-5461 also exhibited significant antitumor effects against 5 out of 6 human tumor xenografts in nude mice. The antitumor activity was similar to or greater than those of chemotherapeutics. Antitumor effects of DT-5461 significantly correlated with intratumoral levels of tumor necrosis factor (TNF) induced by the compound (r = 0.701, p < 0.05). In vitro TNF production by DT-5461-stimulated macrophages was augmented by tumor cells, and the augmentative effect correlated with TNF activity detected in these tumor tissues. Meanwhile, a weaker therapeutic efficacy of DT-5461 was observed against certain tumors that caused a significant increase in the level of immunosuppressive factors in host blood. These findings support the idea that intratumoral TNF plays a crucial role in the antitumor mechanisms of DT-5461 and suggest that its antitumor action is influenced by an augmentative effect of tumor cells on TNF production and by blood levels of immunosuppressive factors.
Kumazawa
E
E
Exploratory Research Laboratories I, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Jimbo
T
T
Akimoto
T
T
Joto
N
N
Tohgo
A
A
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004187:Disaccharides / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D004187:Disaccharides; D008050:Lipid A; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha; C030193:immunosuppressive acidic protein; C077208:DT 5461; D015232:Dinoprostone