Effects of Liposome-Entrapped Muramyl Tripeptide Phosphatidylethanolamine (L-MTP-PE) on the Tumor Growth and Survival of Mice Bearing Syngeneic Tumor in Combination with a Chemotherapeutic or Immunomodulatory Agent

Abstract

Antitumor activities of L-MTP-PE (Liposome entrapped myuramyl tripeptide phosphatidylethanolamine) in the combination treatment with chemo- or immune-therapeutic antitumor agents against various syngeneic tumors were tested.

Against Meth A fibrosarcoma solid tumor system, L-MTP-PE showed slight but statistically significant elongation of survival days against 5-FU monotherapy in spite of its non-effect on tumor growth, when combined with 5-FU. Against liver metastasis model of M5076 carcinoma, L-MTP-PE showed a tendency of elongation of survival days by its single drug treatment, however, elongation with statistical significance was observed in the combination treatment with 5-FU in comparison with control group.

These data suggest that L-MTP-PE seems to elongate the survival days of the solid tumor bearing mice and the liver metastasis model basically due to its saving effect on chemotherapeutic drug-induced immunosuppression. In the combination with an immunotherapeutic agent in mice, TNF production induced by another biological response modifier OK-432 was potentiated when primed with L-MTP-PE. L-MTP-PE also potentiate the antitumor effect of OK-432 possibly through the enhanced production of TNF-α. Combination of L-MTP-PE and OK-432 is considered to be a candidate for a new treatment model for cancer.

Key word

L-MTP-PE - MDP - combination therapy - OK-432

Publication History

Received: 02 December 2021

Accepted: 25 April 2022

Article published online:
29 June 2022

• References

• 1 Ellouz F, Adam A, Clorbaru R.. et al. Minimal structured requirements for adjuvant activity of bacterial peptidoglycan derivatives. Biochem. Biophys. Res. Commun. 59: 1317-1325 1974;
• 2 Fogler WE, Wada R, Brundish DE. et al. Distribution and fate of free and liposome-encapsulated [³H]nor-muramyl dipeptide and [³H]muramyl tripeptide phosphatidylethanolamine in mice. J. Immunol. 135: 1372-1377 1985;
• 3 Wiegand W.. CGP19835A: Disposition studies with ¹⁴C-labeled CGP19835A: Intravenous administration of liposome entrapped substance to rats, rabbits and dogs. CIBA-GEIGY Co. Limited Basle, internal report B. 1986
• 4 Fidler IJ, Sone S, Fogler WE. et al. Efficacy of liposome containing a lipophilic muramyl dipeptide derivative for activating the tumoricidal properties of alveolar macrophages. In Vivo. J. Biol. Resp. Modif 1: 43-55 1982;
• 5 Sone S, Utsugi T, Tandon P. et al. A dried preparation of liposomes containing muramyl tripeptide phosphatidyletyhanolamine as a potent activator of human blood monocytes to the antitumor state. Cancer Immunol. Immunother. 22: 191-196 1986;
• 6 Talmadge JE, Schneider M, Collins M. et al. Augmentation of NK cell activity in tissues specific sites by liposomes incorporating MTP-PE. J. Immunol. 135: 1477-1483 1985;
• 7 MacEwen EG, Kurzman ID., Rosenthal RC. et al. Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. J. Natl. Cancer Inst. 81: 935-938 1989;
• 8 Fidler IJ. Optimization and limitation of systemic treatment of murine melanoma metastasis with liposomes containing muramyl tripeptide phosphatidylethanolamine. Cancer Immunol. Immunother. 21: 169-173 1986;
• 9 Nakajima R, Ishida Y, Yamaguchi F. et al. Beneficial effect of muroctasin on experimental leukopenia induced by cyclophosphamide or irradiation in mice. Arzneim.-Forsch. Drug Res. 38: 986-992 1988;
• 10 Oshima H, Inagawa H, Satoh M. et al. Theoretical grounds and practical methods for induction of endogenous production of human tumor necrosis factor. In “Host defense mechanisms against cancer (Urushizaki, I., Aoki, T and Tsubura, E. eds). Excerpta Medica, Amsterdam, pp 92-100 1985;
• 11 Okutomi H, Inagawa H, Nishizawa T. et al. Priming effect of orally administered muramyl dipeptide (MDP) on induction of endogenous of tumor necrosis factor (TNF). J. Biol. Response Mod. 9: 564-569 1990;
• 12 Ueda U, Yamazaki M. Induction of tumor necrosis factor-αin solid tumor region by the orally administered synthetic muramyl dipeptide analogue, romurtide. Inter. Immunol 1: 97-104 2001;
• 13 Satoh M, Inagawa H, Minagawa H. et al. Endogenous production of TNF in mice lung after BCG-sensitization. J. Biol. Res. Modif 5: 117-123 1986;
• 14 Ruff MR, Gifford GE.. Rabbit tumor necrosis factor: mechanism of action. Infect. Immun. 31: 380-385 1981;
• 15 Berendt MJ, North RJ, Kirstein MDP.. The immunological basis of endotoxin-induced tumor regression. J. Exp. Med 148: 1550-1559 1978;
• 16 Alexander JC, Eugenie SK, Mark DK. et al. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma. Cancer 115: 5339-5348 2009;
• 17 Ando K, Mori K, Corradini N. et al. Mifamuride for the treatment of nonmetastatic osteosarcoma. Expert Opin. Pharmacother. 12: 285-292 2011;
• 18 Xu Z, Fidler IJ. The in situ activation of cytotoxic properties in murine Kupffer cells by the systemic administration of whole mycobacterium bovis organisms or muramyl tripeptide. Cancer Immunol. Immunother. 18: 118-122 1984;
• 19 Asano T, Kleinerman ES. Liposome-encapsulated MTP-PE: A novel biologic agent for cancer therapy. J. immunother. 14: 286-292 1993;
• 20 Netea MG, Ferwerda G, de Jong DJ. et al. Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release. J. Immunol. 174: 6518-6523 2005;
• 21 Okamoto M, Oshikawa T, Tano T. et al. Mechanism of anticancer host response induced by OK-432, a streptococcal preparation, mediated by phagocytosis and toll-like receptor 4 signaling. J. Immunol. 29: 78-86 2006;
• 22 Hsu LC, Ali SR, McGillivray S. et al. A NOD2-NALP1 complex mediates caspase-1-dependent IL-1β secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc. Nat. Acad. Sci. 105: 7803-7808 2008;
• 23 Fidler IJ, Brown NO, Hart IR. Species variability for toxicity of free and liposome-encapsulated muramyl peptides administered intravenously. J. Biol. Resp. Modif 4: 298-309 1985;
• 24 Gay B, Cardot J-M, Schnell C. et al. Comparative pharmacokinetics of free muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) and liposomal MTP-PE. J. Pharmac. Sci. 82: 997-1001 1993;
• 25 A package Insert, Picibanil, Chugai https://www.info.pmda.go.jp/go/pack/4299400D1038_1_07/ (accessed February 16, 2020)
• 26 Zhu S, Zhang T, Zheng L. et al. Combination strategies to maximize the benefits of cancer immunotherapy. J. Hematol. Oncol. 14: 156 2021;