Antitumor effect of DT-5461a, a synthetic low-toxicity lipid A analog, involves endogenous tumor necrosis factor induction subsequent to macrophage activation.
We previously showed that the synthetic lipid A derivative DT-5461a exhibited significant antitumor effects against various murine solid tumors, probably via activation of host immune systems. To clarify the participation of the macrophage-stimulating effect of DT-5461a in the antitumor mechanisms, we studied the ability of this compound to induce cytostatic macrophages and TNF production in murine systems. Cytostatic macrophages were induced by treatment with DT-5461a either in vitro or in vivo. DT-5461a also induced TNF production by resident peritoneal macrophages or spleen cells obtained from untreated mice. When spleen cells prepared from DT-5461a-treated mice were re-stimulated in vitro with DT-5461a, no TNF was produced by cells obtained at 1 day after the treatment. This may be due to transient refractoriness of macrophages to the compound, since the response to re-stimulation with DT-5461a recovered in cells obtained at 3 or 5 days after treatment. Moreover, while the serum TNF production and antitumor effects by DT-5461a decreased on daily administration, they were elicited by intermittent administration at intervals of 3 days or more. This suggests that the antitumor effects of DT-5461a depend on the TNF-producing activity of macrophages. These results indicate that DT-5461a possesses significant macrophage-stimulating activity, and that macrophages so activated mediate the DT-5461a-induced augmentation of host response against solid tumors.
Akimoto
T
T
Exploratory Research Laboratories I, Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan.
Kumazawa
E
E
Jimbo
T
T
Joto
N
N
Tohgo
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002240:Carbohydrate Sequence; D003601:Cytotoxicity Tests, Immunologic; D004187:Disaccharides / Q000494:pharmacology*; D005354:Fibrosarcoma / Q000276:immunology; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation / Q000276:immunology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000187:drug effects*
D000970:Antineoplastic Agents; D004187:Disaccharides; D008050:Lipid A; D014409:Tumor Necrosis Factor-alpha; C077208:DT 5461