Muramyl dipeptides

Endotoxin and Muramyl Dipeptide Derivatives. Bacterial cell wall constituents such as the Hpopolysaccharide endotoxin and muramyl dipeptide, which stimulate host defense systems, show radioprotective activity in animals (204). Although endotoxin is most effective when given - 24 h before irradiation, it provides some protection when adrninistered shortiy before and even after radiation exposure. Endotoxin s radioprotective activity is probably related to its Hpid component, and some of its properties may result from PG and leukotriene induction (204). 

Muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic analogue of muramyl dipeptide and an effective systemic macrophage activator, induces a variety of cytokines such as IL-1, IL-6, and TNE, as well as PGE2 (205). Preirradiation treatment of mice using MTP-PE encapsulated in Hposomes, which can intensify radioprotective abiHty, stimulates the monocyte/macrophage system and accelerates the recovery of hemopoietic cells. 

Gram-positive (whole organisms peptidoglycans [e.g., muramyl dipeptide] lipoteichoic acids exotoxins enterotoxins erythrogenic toxins group B polysaccharides)... 

A human contraceptive vaccine based on lactide polymers is currently being developed. The antigen is a 37-amino-acid peptide of B-HCG conjugated to diphtheria toxoid. The antigen is administered wtih microencapsulated muramyl dipeptide as an adjuvant. Studies in rabbits have shown 9-12 months of elevated antibody liter following... 

Muramyl dipeptide derivatives have also been microencapsulated in lactide/glycolide copolymers for use alone as an immuno potentiator. L-lactide/glycolide copolymers were used to deliver MDP-B30, a lipophilic compound, from very small microspheres (less than 5 pm in diameter). The amount of MDP-B30 required for tumor growth inhibitory activity of mouse peritoneal macrophages was 2000 times less for the controlled release MDP-B30 microspheres than for the unen-capsulated drug (134). 

Tabata, Y. and Ikada, Y., Activation of macrophage in vitro to acquire antitumor activity by a muramyl dipeptide derivative encapsulated in microspheres composed of lactide copolymer, J Control. Rel.. 6, 189, 1987. 

Daemen, T., Veninga, A., Dijkstra, J., and Scherphof, G. (1989) Differential effects of liposomeincorpo-ration on liver macrophage activating potencies of rough lipopolysaccharide, lipid A, and muramyl dipeptide Differences in susceptibility to lysosomal enzymes. Immunol. 142, 2469-2474. 

A variety of lipid adjuvants and protein mediators have also been shown to influence the immune response to antigens encapsulated in liposomes. The most widely used examples of such adjuvants for practical immunization procedures are endotoxin (including lipid A and lipopolysaccharide) and numerous types of lipophilic derivatives of muramyl dipeptide. 

Key, M.E. et al., Isolation of tumoricidal macrophages from lung melanoma metastases of mice treated systemically with liposomes containing a lipophilic derivative of muramyl dipeptide, J. Natl. Cancer Inst., 69, 1198, 1982. 

Wood, D.D. et al., Role of Interleukin-1 in the Adjuvanticity of Muramyl Dipeptide in Vivo, in Interleukins, Lymphokines and Cytokines, Oppenheim, J J. and Cohen, S., Eds., Raven Press, New York, 1983... 

Worth, L.L. et al., ImmTher, a lipophilic disaccharide derivative of muramyl dipeptide, up-regulates specific monocyte cytokine genes and activates monocyte- mediated tumoricidal activity, Cancer Immunol Immunother., 48, 312, 1999. 

G. M. Barratt, C. Morin, M. Appel, and I. Seyler, Intracellular delivery of a muramyl dipeptide derivative by poly(DL-lactide) nanocapsules, in In vitro and ex vivo test systems to rationalize drug design and delivery, Paris, 1993, pp. 265-268. 

Aluminium phosphate, AIPO4 Aluminium hydroxide, Al(OH)3 Alum, A1K(S04)2.12H20 Calcium phosphate, CaP04 Mycobacterial species Mycobacterial components (e.g. trehalose dimycolate, muramyl dipeptide) Corynebacterium species Bordetella pertussis Lipopolysaccharide... 

Latterly, some oil-in-water adjuvants have been developed. Many are squalene-in-water emulsions. Emulsifiers most commonly used include polyalcohols, such as Tween and Span. In some cases, immunostimulatory molecules (including muramyl dipeptide and trehalose... 

Fractionation of mycobacteria resulted in the identification of two cellular immunostimulatory components, trehalose dimycolate (TDM) and muramyl dipeptides (MDP). Both are normally found in association with the mycobacterial cell wall. TDM is composed of a molecule of trehalose (a disaccharide consisting of two molecules of a-D-glucose linked via an a 1-1 glycosidic bond), linked to two molecules of mycolic acid (a long-chain aliphatic hydrocarbon-based acid) found almost exclusively in association with mycobacteria. TDM, while retaining its adjuvanticity, is relatively non-toxic. 

Bacillus Calmette-Guerin (BCG) and its active component, muramyl dipeptide, have been shown to have aspecific immunostimulant activity. It is mainly used for the local treatment of bladder cancer. It binds to fibronectine in the bladder epithelium. Hypersensitivity reactions and immune complex disease are its major adverse reactions. 

Bacillus Calmette-Guerin (BCG) is a viable attenuated strain of Mycobacterium bovis. Nonviable strains of the bacterium also have been shown to augment the immune response. The smallest active compound derived from BCG thus far has been identified as muramyl dipeptide. The T cell is a principal target for BCG. It also appears to stimulate natural killer cells, which in turn can kill malignant cells. It has been suggested that BCG cross-reacts immunologically with tumor cell antigens. 

When crude endotoxin from the heptose-less mutant of Salmonella typhimurium is combined with trehalose dimycolate from mycobacteria in oil droplets and injected directly into established tumors (line 10 hepatocellular carcinoma) in syngeneic guinea pigs, rapid regression of the tumors occurs and over 90% of the animals are cured. The three required components for activity in this tumor model are (a) the endotoxin (b) the mycobacterial adjuvant, trehalose dimycolate and (c) a compound satisfying the minimal structural requirement (muramyl dipeptide) for adjuvant activity by bacterial cell wall materials. The mycobacterial cell wall skeleton is able to replace the latter two components. 

Derrien, D., Midoux, P., Petit, C., et al. Muramyl dipeptide bound to poly-L-lysine substituted with mannose and gluconoyl residues as macrophage activators. Glycoconj. J. 6 241-255, 1989. 

Monsigny, M., Roche, A. C., and Bailly, P. Tumoricidal activation of murine alveolar macrophages by muramyl dipeptide substituted mannosylated serum albumin. Biochem. Biophys. Res. Commun. 121 579-584, 1984. 

BCG is a viable strain of Mycobacterium bovis that has been used for immunization against tuberculosis. It has also been employed as a nonspecific adjuvant or immunostimulant in cancer therapy but has been successful only in intravesical therapy for superficial bladder cancer. BCG appears to act at least in part via activation of macrophages to make them more effective killer cells in concert with lymphoid cells in the cellular efferent limb of the immune response. Lipid extracts of BCG as well as nonviable preparations of Corynebacterium parvum may have similar nonspecific immunostimulant properties. A chemically defined derivative of the BCG cell wall, [Lys18]-muramyl dipeptide, has been licensed in Japan to enhance bone marrow recovery after cancer chemotherapy. 

To increase the antiparasitic effect of methotrexate [254,255] and the more potent drugs doxorubicin [181] and muramyl dipeptide (MDP) [182], these drugs were coupled to manHSA. The beneficial effects of selective uptake of these drugs in KC was examined in mice infected with Leishmania parasites. These conjugates all inhibited the growth of these parasites in the macrophages predominantly in the liver but also in the spleen after repeated injections of the conjugate in leishmaniasis-infected mice. 

K. Sarkar and P. K. Das, Protective effect of neoglycoprotein-conjugated muramyl dipeptide against Leishmania donovani infection the role of cytokines../. Immunol. 158 5351-5365 (1997). 

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