COMBINED EFFECTS OF SYNTHETIC LIPID-A ANALOGS OR BACTERIAL LIPOPOLYSACCHARIDE WITH GLUCOSAMINYLMURAMYL DIPEPTIDE ON ANTITUMOR-ACTIVITY AGAINST METH-A FIBROSARCOMA IN MICE

The combined effects of the synthetic glucosaminylmuramyl dipeptide (GMDP) on the antitumor activity of chemically synthesized lipid A analogs, compound A-103 (glucosamine-4-phosphate with (R)-3-tetradecanoyloxytetradecanoyl group at the C-2 and C-3 positions), Escherichia coli-type lipid A (506), Salmonella typhimurium LT-2 lipopolysaccharide (LPS) against Meth A fibrosarcoma in mice were examined. Meth A fibrosarcoma cells (5 x 10(5)) were inoculated intradermally into BALB/c mice on day 0, and compound A-103 and/or GMDP was administered intravenously (i.v.) on days 7 and 9. Two i.v. injections of A-103 (50 mug) alone or GMDP (10 mug) alone induced 42.8 or 51.8% inhibition of the rate of tumor growth, however, A-103 (100 mug) with GMDP (10 mug) exhibited a high 68.7% inhibition rate 19 days after tumor inoculation. The inhibition of the tumor growth rate by the combination A-103 (100 mug) or 506 (50 mug) with GMDP (10 mug) was stronger than that of A-103 or 506 with MDP (10 mug). The combination of LPS (1 or 10 mug) with GMDP (10 mug) exhibited a higher inhibition rate than that of LPS with MDP, and three or four tumor-free mice out of five mice were observed, suggesting that the combined effect of GMDP is more potent than that of MDP. With the addition of GMDP, A-103 did not enhance the production of tumor necrosis factor (TNF) on the basis of L929 cell lysis. On the other hand, the combination of 506 or LPS with GMDP induced higher TNF production than that of 506 or LPS with MDP, indicating that 506 or LPS is able to enhance TNF production in the presence of GMDP.