Significant antitumor effect of a synthetic lipid A analogue, DT-5461, on murine syngeneic tumor models

Abstract

The antitumor effect of a synthetic lipid A analogue, DT-5461, was investigated using syngeneic tumor models in mice. Intravenous injection of DT-5461 into mice transplanted with solid tumors of MethA fibrosarcoma, MH134 hepatoma, MM46 mammary carcinoma, Lewis lung carcinoma (3LL), and colon adenocarcinomas 26 and 38 resulted in significant reductions in the weight of all tumors except Colon 26, with marked hemorrhagic necrosis of tumor tissues. Efficacy was almost equal to that of an Escherichia coli-type synthetic lipid A (compound 506), and also to those of some chemotherapeutics including Adriamycin, mitomycin C, fluorouracil and cisplatin. Furthermore, DT-5461 was more effective than other immunotherapeutics, including picibanil (OK-432) and lentinan. However, its antitumor effects were inferior to those of Adriamycin or OK-432 against the malignant ascites caused by intraperitoneal inoculation with MethA or with MH134 cells; life span was not prolonged by either intraperitoneal or intravenous administration. In addition, although DT-5461 showed direct inhibitory effects on the in vitro growth of MethA or MH134, these were much weaker than those of Adriamycin. These findings clearly indicated that DT-5461 with systemic administration is a highly effective antitumor agent on solid tumors, and suggest that the antitumor effect of DT-5461 with potent necrotizing activity might derive from indirect mechanisms related to the activation of host immune systems and not to the weak direct cytotoxicity.

Mechanisms of the antitumoral effect of lipid A

“…Although TNF-a is involved in the antitumoral effect of lipid A, other factors are clearly involved. Thus while DT-5461 reduced the size of several murine tumors via a necrotic process and TNF-a secretion, (11,13,17) anti-TNF-a antibodies did not prevent tumor regression. (15) Furthermore ONO-4007 injected i.v.…”

Progress in the synthesis and biological evaluation of lipid A and its derivatives

“…) as phosphonooxyethyl glycosides to replace the labile α‐glycosyl phosphate . It was anticipated that these lipid A analogs might have improved bioactivities, such as antitumor activity, owing to their enhanced chemical stability.…”

“…According to the literature, E. coli lipid A and its derivatives had antitumor activities, thus the cytotoxicity of natural lipid A 1 and its synthetic analogs 54 – 56 to methylcholanthrene‐induced murine fibrosarcoma (Meth A fibrosarcoma) was studied in vivo . Compounds were administered to the mice at a dose of 100 μg/mL through the tail veins three times (7, 12, and 17 days after tumor inoculation).…”

“…69 It was anticipated that these lipid A analogs might have improved bioactivities, such as antitumor activity, [70][71][72][73] owing to their enhanced chemical stability. According to the literature, [70][71][72][73] E. coli lipid A and its derivatives had antitumor activities, thus the cytotoxicity of natural lipid A 1 and its synthetic analogs 54-56 to methylcholanthrene-induced murine fibrosarcoma (Meth A fibrosarcoma) was studied in vivo. 69 Compounds were administered to the mice at a dose of 100 g/mL through the tail veins three times (7,12, and 17 days after tumor inoculation).…”

A novel synthetic lipid A analog with low endotoxicity, DT-5461, prevents lethal endotoxemia

“…A synthetic diglucosamine-based analog of Escherichia coli lipid A, DT-5461, possesses properties, such as lethal toxicity and pyrogenicity, that are considerably less endotoxic than those of LPS or synthetic lipid A and expresses effects against various murine syngeneic solid tumors (18,19). We previously demonstrated that DT-5461 significantly inhibited liver metastasis of L5178Y-ML25 lymphoma cells and lung metastasis of B16-BL6 melanoma cells during experimental metastasis and spontaneous metastasis in mice (31).…”