Multiple
intravenous injections (30 micrograms, ten times) in ICR mice of
trehalose dimycolate and
glucose monomycolate from Nocardia rubra, containing C36-48
mycolic acids, showed a prominent antitumor effect on a subcutaneously implanted sarcoma-180, an allogeneic
sarcoma of mice with a significant
granuloma formation in lungs, spleen and liver. On the other hand, mycoloyl
glycolipids other than
glucose monomycolate and
trehalose dimycolate, such as
mannose or
fructose mycolate, showed no significant activity for
tumor regression or
granuloma formation in mice.
Trehalose dimycolate and
glucose monomycolate from N. rubra, and
glucose monomycolate with C56-60
mycolic acids from Rhodococcus terrae also showed a distinctive priming activity for
tumor necrosis factor (TNF), when
lipopolysaccharide from Escherichia coli was administered as an eliciting agent. The TNF activity in the sera of mice was abrogated almost completely by anti-(murine
TNF alpha) antibody with
protein-A-
agarose. Again in contrast,
mannose and
fructose mycolate from N. rubra and
glucose monomycolate with C30-34
mycolic acids from Rhodococcus equi did not show such activities in mice. Meth-A, a syngeneic
fibrosarcoma of BALB/c mice, was less sensitive to administration of
glycolipids than sarcoma-180. These results indicated that the existence of a
glucose or
trehalose molecule was necessary for the expression of immunomodifying activities among various mycoloyl
glycolipids differing in
carbohydrate structure. However, since the administration of
lipopolysaccharide was essentially required as an eliciting agent for the induction of TNF, while no eliciting agent was required for the antitumor activities, TNF does not seem to contribute directly to the antitumor activities of mycoloyl
glycolipids in our systems. There was, however, a parallel structure-activity relationship among
granuloma-forming, antitumor and TNF-priming activities, indicating that the structures of both the
carbohydrate moiety and the mycoloyl residues influenced an initial step, such as macrophage activation, commonly and profoundly.