Enhancement of nonspecific resistance to bacterial infections and tumor regressions by treatment with synthetic lipid A-subunit analogs. Critical role of N- and 3-O-linked acyl groups in 4-O-phosphono-D-glucosamine derivatives.
Enhancement of nonspecific resistance against Pseudomonas aeruginosa infection and regression of growth of Meth A fibrosarcoma by chemically synthesized lipid A-subunit analogs, 4-O-phosphono-D-glucosamine derivatives carrying 3-O- and N-linked acyl groups, were investigated. Compounds carrying an (R)-3-hydroxytetradecanoyl (C14-OH) group at the 2-N-position with (R)-3-tetradecanoyloxytetradecanoyl [C14-O-(C14)] or (R)-3-dodecanoyloxytetradecanoyl [C14-O-(C12)] groups at the 3-O-position, termed GLA-60 or GLA-63, respectively, showed strong activity about one-tenth that of natural lipid A. The protective activity of compounds carrying an (R)-3-hexadecanoyloxytetradecanyl group instead of a C14-O-(C14) or C14-O-(C12) group was very weak. GLA-59 carrying the same acyl components as those of GLA-60 but with reversed binding sites showed significant but not so strong protective activity. The activity of compounds possessing a tetradecanoyl group instead of a C14-OH group in GLA-60 or GLA-63 was weaker than that of GLA-60 or GLA-63. Intravenous or intratumoral administration of GLA-59, GLA-60 and GLA-63 induced significant regression of Meth A fibrosarcoma in terms of tumor size, tumor weight and number of cured mice. The activity of GLA-59 was almost equivalent to that of GLA-60. None of the tested compounds exhibited significant pyrogenicity at a dose of 10 micrograms/kg in rabbits.
Kitasato Institute, Tokyo, Japan.
M
M
Nakatsuka
Y
Y
Kumazawa
M
M
Matsuura
J Y
JY
Homma
M
M
Kiso
A
A
Hasegawa
D000276:Adjuvants, Immunologic; D000818:Animals; D001424:Bacterial Infections / Q000276:immunology* / Q000628:therapy; D005260:Female; D005354:Fibrosarcoma / Q000276:immunology* / Q000628:therapy; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007113:Immunity, Innate / Q000187:drug effects; D008050:Lipid A / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D009368:Neoplasm Transplantation; D011552:Pseudomonas Infections / Q000276:immunology / Q000628:therapy
D000276:Adjuvants, Immunologic; D008050:Lipid A; D005944:Glucosamine