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.