Muramyl tripeptide

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. 

Van Hoogevest, P., and Fankhauser, P. (1989). An industrial liposomal dosage form for muramyl-tripeptide-phosphatidylethanola-mine (MTP-PE), in Liposomes in the Therapy of Infectious Diseases and Cancer (G. Lopez-Berestein and I. J. Fidler, eds.), Alan R. Liss, New York, pp. 453-466. 

A number of derivatives were synthesized in the hope of identifying a modified form that retained its adjuvanticity but displayed lesser toxicity. Some such derivatives, most notably threonyl-MDP, muramyl tripeptide and murabutide, display some clinical promise in this regard. 

MDP-PE, muramyl tripeptide phosphatidyl, Ethanolamine Lipoidal tripeptide Macrophage activating agent Osteosarcomas... 

Kleinerman, E.S., Biologic therapy for osteosarcoma using liposome-encapsulated muramyl tripeptide, Hematol. Oncol. Clin. North Am., 9, 927, 1995. 

Kleinerman, E.S. et al., Combination therapy with ifosfamide and liposome-encapsulated muramyl tripeptide Tolerability, toxicity, and immune stimulation, J. Immunother. Emphasis. Tumor Immunol., 17, 181, 1995. 

Gianan, M.A. and Kleinerman, E.S., Liposomal muramyl tripeptide (CGP 19835A lipid) therapy for resectable melanoma in patients who were at high risk for relapse An update, Cancer Biother. Radiopharm., 13, 363, 1998. 

Killion, J.J. et al., Maintenance of intestinal epithelium structural integrity and mucosal leukocytes during chemotherapy by oral administration of muramyl tripeptide phosphati-dylethanolamine, Cancer Biother. Radiopharm., 11, 363, 1996. 

The treatment of tumours in the liver with drug targeting preparations is hampered by the lack of tumour specifity of most preparations. Liposomes incorporating the immunomodula-tor muramyl tripeptide phosphatidylethanolamine have been used as an aspecific approach to increasing the number of tumouricidal macrophages in the liver in order to prevent the development of metastases [99].To date, the greatest tumour cell specificity has been obtained... 

Encapsulation of immunomodulators, e.g. muramyl tripeptide analogues, into liposomes has been designed to stimulate host immunity [108] and can be used in combination with other treatment modalities. The systemic activation of macrophages provides an additional therapeutic modality for the eradication of cancer and cancer metastases. 

Liposome-encapsulated immunomodulators are currently under investigation in different patient groups although this development has certainly not advanced as far as that with the liposomal anthracyclines. MLV-MTP-PE (multilamellar vesicles-muramyl tripeptide-phos-phatidylethanolamine) was studied in several clinical trials in osteosarcoma patients who developed pulmonary metastases during adjuvant chemotherapy [108], The intravenous administration of MLV-MTP-PE induced tumouricidal properties in monocytes as well as increase in serum IL-1 shortly after intravenous infusion. Furthermore elevations in C-reactive protein, 32-microglobulin and ceruloplasmin were frequently observed. Even higher anti-tumour activity was observed in combination with ifosfamide. These preliminary results suggests that liposome-encapsulated immunomodulators in combination with chemotherapy may be an appropriate treatment for recurrent disease. 

MLV-MTP-PE multilamellar vesicles-muramyl tripeptide-phosphatidyletha-nolamine... 

Nardin, A., Lefebvre, M. L., Labroquere, K., Faure, O., and Abastado, J. P. (2006). Liposomal muramyl tripeptide phosphatidylethanolamine targeting and activating macrophages for adjuvant treatment of osteosarcomaCurr. Cane. DrugTarg., 6, 123-133. 

The wild-type UDP-MurNAc-L-Ala-y-D-Glu-L-Lys-D-Ala-D-Ala (UDP-MurNAc-pentapeptide) was first isolated from S. aureus in 1952 by James Park [77], Nicolas Gisch et al. reported the synthesis of the biotinylated Lys-type and DAP-type muramyl tripeptides through their UDP derivatives [78], Both compounds activated Nod2 in a cell-based assay, although the required minimal motif for the activation of Nod2 is muramyl dipeptide [79], The chemical synthesis of the UDP-MurNAc-pentapeptide 7 (Scheme 14.1) [19] was followed by the chemoenzymatic synthesis by Chi-Huey Wong [80] and Michio Kurosu [81], Wong et al. also synthesized the vancomycin-resistant UDP-MurNAc-L-Ala-y-D-Glu-L-Lys-D-Ala-D-Lac... 

The antitumor properties of muramyl tripeptide are thought to be related to its immunoenhancing effects, in particular on the monocyte/macrophage system. Its most common adverse effect is a flu-like syndrome, usually during the first administration. In one trial in nine patients, four had mild to moderate respiratory distress, two of whom had pre-existing asthma and symptoms suggestive of asthma exacerbation (1). 

Sone S, Tandon P, Utsugi T, et al. Synergism of recombinant human interferon gamma with liposome-encapsulated muramyl tripeptide in activation of the tumoricidal properties of human monocytes. Int J Cancer 1986 38 495-500. 

Finally the dipeptide is added to the lysine residue of the UDPiV-acetyl-muramyl tripeptide by way of a specific enzyme, with characteristics similar to those of the other amino-acyl ligases described above. The UDPA-acetyl-muramyl pentapeptide so formed can now enter the next part of the biosynthetic pathway, in which the repeating unit of the polysaccharide of the peptidoglycan is formed by way of an undecaprenol-dependent cycle. 

In some peptidoglycans, the a-carboxyl function of the D-glutamyl residue is substituted with glycine (M. lysodeikticus), glycine amide A. arthrocyaneus), or D-alanine amide Arthrobacter sp.). The corresponding N-acetyl-muramyl-tripeptides (56—58), have been synthesized 32, 44, 4S). 

Three N-acetyl-muramyl-tripeptides were synthesized which bear on the carboxyl function of MDP either a L-lysyl, (63) (55, 44) a L-alanyl, (64), or a D-alanyl, (65) (45) residue. All of these compounds were obtained by the general stepwise method of synthesis. The hydrogenolysis step leading to (61 and 63) was complete only in presence of 0.5 equivalents of hydrochloric acid (52). 

Mouse alveolar macrophages were rendered tumoriddal after the intravenous administration of liposomes containing muramyl tripeptide phosphatidyl-ethanolamine, a lipophilic derivative of muramyl dipeptide (Fidler et al. 1989). 

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