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Mifamurtide

Descripition of mifamurtide: mifamurtide is a liposomal formulation containing a muramyl dipeptide (MDP) analogue with potential immunomodulatory and antineoplastic activities.. Muramyl tripeptide phosphatidylethanolamine (MTP-PE), a derivative of the mycobacterial cell wall component MDP, activates both monocytes and macrophages. Activated macrophages secrete cytokines and induce the recruitment and activation of other immune cells, which may result in indirect tumoricidal effects. Liposomal encapsulation of MTP-PE prolongs its half-life and enhances tissue targeting. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).  

Current developer:    IDM Pharma /Takeda

Mifamurtide (trade name Mepact, marketed by Takeda) is a drug against osteosarcoma, a kind of bone cancer mainly affecting children and young adults, which is lethal in about a third of cases. The drug was approved in Europe in March 2009.

The drug was invented by Ciba-Geigy (now Novartis) in the early 1980s and sold to Jenner Biotherapies in the 1990s. In 2003, IDM Pharma bought the rights and developed it further.  IDM Pharma was acquired by Takeda along with mifamurtide in June 2009.  Mifamurtide had already been granted orphan drug status by the U.S. Food and Drug Administration (FDA) in 2001, and the European Medicines Agency (EMEA) followed in 2004. It was approved in the 27 European Union member states plus Iceland, Liechtenstein and Norway via a centralized marketing authorization in March 2009. The drug was denied approval by the FDA in 2007. See wikipedia.com for detail.

1: Anderson PM, Tomaras M, McConnell K. Mifamurtide in osteosarcoma - a practical review. Drugs Today (Barc). 2010 May;46(5):327-37. PubMed PMID: 20517534.

2: Frampton JE. Mifamurtide: a review of its use in the treatment of osteosarcoma. Paediatr Drugs. 2010 Jun;12(3):141-53. doi: 10.2165/11204910-000000000-00000. PubMed PMID: 20481644.

3: Molecule of the month. Mifamurtide. Drug News Perspect. 2010 Apr;23(3):199. PubMed PMID: 20440421.

4: Meyers PA. Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma. Expert Rev Anticancer Ther. 2009 Aug;9(8):1035-49. Review. PubMed PMID: 19671023.

5: Chou AJ, Kleinerman ES, Krailo MD, Chen Z, Betcher DL, Healey JH, Conrad EU 3rd, Nieder ML, Weiner MA, Wells RJ, Womer RB, Meyers PA; Children's Oncology Group. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: a report from the Children's Oncology Group. Cancer. 2009 Nov 15;115(22):5339-48. PubMed PMID: 19637348; PubMed Central PMCID: PMC2783515.

6: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2008 May;30(4):313-31. PubMed PMID: 18773127.

7: Dvoroznáková E, Porubcová J, Snábel V, Fedorocko P. Imunomodulative effect of liposomized muramyltripeptide phosphatidylethanolamine (L-MTP-PE) on mice with alveolar echinococcosis and treated with albendazole. Parasitol Res. 2008 Sep;103(4):919-29. Epub 2008 Jun 29. PubMed PMID: 18587669.

8: Mifamurtide: CGP 19835, CGP 19835A, L-MTP-PE, liposomal MTP-PE, MLV 19835A, MTP-PE, muramyltripeptide phosphatidylethanolamine. Drugs R D. 2008;9(2):131-5. Review. PubMed PMID: 18298131.

9: Mori K, Ando K, Heymann D. Liposomal muramyl tripeptide phosphatidyl ethanolamine: a safe and effective agent against osteosarcoma pulmonary metastases. Expert Rev Anticancer Ther. 2008 Feb;8(2):151-9. Review. PubMed PMID: 18279055.

10: Anderson P. Liposomal muramyl tripeptide phosphatidyl ethanolamine: ifosfamide-containing chemotherapy in osteosarcoma. Future Oncol. 2006 Jun;2(3):333-43. Review. PubMed PMID: 16787112.

11: Nardin A, Lefebvre ML, Labroquère K, Faure O, Abastado JP. Liposomal muramyl tripeptide phosphatidylethanolamine: Targeting and activating macrophages for adjuvant treatment of osteosarcoma. Curr Cancer Drug Targets. 2006 Mar;6(2):123-33. Review. PubMed PMID: 16529542.

12: Romet-Lemonne JL, Mills B, Fridman WH, Munsell M. Prospectively planned analysis of data from a phase III study of liposomal muramyltripeptide phosphatidylethanolamine in the treatment of osteosarcoma. J Clin Oncol. 2005 Sep 10;23(26):6437-8. PubMed PMID: 16155031.

13: Fedorocko P, Hoferová Z, Hofer M, Brezáni P. Administration of liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE) and diclofenac in the combination attenuates their anti-tumor activities. Neoplasma. 2003;50(3):176-84. PubMed PMID: 12937850.

14: Macková NO, Fedorocko P. Effect of liposomal muramyl tripeptide phosphatidylethanolamine and indomethacin on hematopoietic recovery in irradiated mice. Physiol Res. 2002;51(5):511-21. PubMed PMID: 12470204.

15: Worth LL, Jeha SS, Kleinerman ES. Biologic response modifiers in pediatric cancer. Hematol Oncol Clin North Am. 2001 Aug;15(4):723-40, ix. Review. PubMed PMID: 11676281.

16: Klimp AH, De Vries EG, Scherphof GL, Daemen T. Chemo-immunotherapy of ovarian cancer in a murine tumour model. Anticancer Res. 2000 Jul-Aug;20(4):2585-92. PubMed PMID: 10953330.

17: Karpoff HM, Jarnagin W, Delman K, Fong Y. Regional muramyl tripeptide phosphatidylethanolamine administration enhances hepatic immune function and tumor surveillance. Surgery. 2000 Aug;128(2):213-8. PubMed PMID: 10922994.

18: Gianan MA, Kleinerman ES. Liposomal muramyl tripeptide (CGP 19835A lipid) therapy for resectable melanoma in patients who were at high risk for relapse: an update. Cancer Biother Radiopharm. 1998 Oct;13(5):363-8. PubMed PMID: 10851426.

19: Kurzman ID, Shi F, Vail DM, MacEwen EG. In vitro and in vivo enhancement of canine pulmonary alveolar macrophage cytotoxic activity against canine osteosarcoma cells. Cancer Biother Radiopharm. 1999 Apr;14(2):121-8. PubMed PMID: 10850295.

20: Dieter P, Hempel U, Malessa B, Fitzke E, Tran-Thi TA, MacLouf J, Créminon C, Kanaoka Y, Urade Y. Lipopolysaccharide- and liposome-encapsulated MTP-PE-induced formation of eicosanoids, nitric oxide and tumor necrosis factor-alpha in macrophages. Adv Exp Med Biol. 1999;469:443-8. PubMed PMID: 10667366.

21: Eue I, Kumar R, Dong Z, Killion JJ, Fidler IJ. Induction of nitric oxide production and tumoricidal properties in murine macrophages by a new synthetic lipopeptide JBT3002 encapsulated in liposomes. J Immunother. 1998 Sep;21(5):340-51. PubMed PMID: 9789196.

22: Durham RM, Lechner AJ, Johanns CA, Chen Z, Matuschak GM. Effect of MTP on TNF-alpha in perfused rat liver after bacteremia and ischemia/reperfusion. J Surg Res. 1998 May;76(2):179-84. PubMed PMID: 9698520.

23: Nesburn AB, Burke RL, Ghiasi H, Slanina SM, Wechsler SL. A therapeutic vaccine that reduces recurrent herpes simplex virus type 1 corneal disease. Invest Ophthalmol Vis Sci. 1998 Jun;39(7):1163-70. PubMed PMID: 9620075.

24: Teske E, Rutteman GR, vd Ingh TS, van Noort R, Misdorp W. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE): a randomized clinical trial in dogs with mammary carcinoma. Anticancer Res. 1998 Mar-Apr;18(2A):1015-9. PubMed PMID: 9615757.

25: Obert M, Pleuger H, Hanagarth HG, Schulte-Mönting J, Wiesmüller KH, Braun DG, Brandner G, Hess RD. Protection of mice against SV40 tumours by Pam3Cys, MTP-PE and Pam3Cys conjugated with the SV40 T antigen-derived peptide, K(698)-T(708). Vaccine. 1998 Jan-Feb;16(2-3):161-9. PubMed PMID: 9607025.

26: ten Hagen TL, van Vianen W, Savelkoul HF, Heremans H, Buurman WA, Bakker-Woudenberg IA. Involvement of T cells in enhanced resistance to Klebsiella pneumoniae septicemia in mice treated with liposome-encapsulated muramyl tripeptide phosphatidylethanolamine or gamma interferon. Infect Immun. 1998 May;66(5):1962-7. PubMed PMID: 9573076; PubMed Central PMCID: PMC108150.

27: Macková NO, Fedorocko P. Effects of immunomodulators on postirradiation recovery in the thymus. Physiol Res. 1997;46(3):193-7. PubMed PMID: 9728506.

28: Dieter P, Ambs P, Fitzke E, Schwende H. Lipopolysaccharide and liposome-encapsulated MTP-PE-induced cytotoxicity and release of eicosanoids, tumor necrosis factor- alpha and nitric oxide in liver macrophages. Adv Exp Med Biol. 1997;407:485-90. PubMed PMID: 9321995.

29: Dzierzbicka K, Gozdowska M, Kołodziejczyk AM. [L-MTP-PE--a potential antineoplastic agent]. Postepy Hig Med Dosw. 1997;51(2):227-36. Review. Polish. PubMed PMID: 9235567.

30: Killion JJ, Bucana CD, Radinsky R, Dong Z, O'Reilly T, Bilbe G, Tarcsay L, Fidler IJ. Maintenance of intestinal epithelium structural integrity and mucosal leukocytes during chemotherapy by oral administration of muramyl tripeptide phosphatidylethanolamine. Cancer Biother Radiopharm. 1996 Dec;11(6):363-71. PubMed PMID: 10851497.

31: Fedorocko P, Macková NO. Combined modality radioprotection: enhancement of survival and hematopoietic recovery in gamma-irradiated mice by the joint use of liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE) and indomethacin. Int J Immunopharmacol. 1996 May;18(5):329-37. PubMed PMID: 8933212.

32: Goldbach P, Dumont S, Kessler R, Poindron P, Stamm A. In situ activation of mouse alveolar macrophages by aerosolized liposomal IFN-gamma and muramyl tripeptide. Am J Physiol. 1996 Mar;270(3 Pt 1):L429-34. PubMed PMID: 8638735.

33: ten Hagen TL, Vossen AC, van Vianen W, Tibbe GJ, Savelkoul HF, Heremans H, Bakker-Woudenberg IA. Enhancement of nonspecific resistance by liposome-encapsulated immunomodulators does not affect skin graft rejection in mice. Transplantation. 1995 Dec 15;60(11):1211-4. PubMed PMID: 8525512.

34: Passlick B, Labeta MO, Izbicki JR, Ostertag P, Löffler T, Siebeck M, Pichlmeier U, Schweiberer L, Ziegler-Heitbrock HW. Prevention of experimental endotoxin shock by a monocyte activator. Antimicrob Agents Chemother. 1995 Nov;39(11):2535-40. PubMed PMID: 8585740; PubMed Central PMCID: PMC162979.

35: Ott G, Barchfeld GL, Van Nest G. Enhancement of humoral response against human influenza vaccine with the simple submicron oil/water emulsion adjuvant MF59. Vaccine. 1995 Nov;13(16):1557-62. PubMed PMID: 8578842.

36: Vail DM, MacEwen EG, Kurzman ID, Dubielzig RR, Helfand SC, Kisseberth WC, London CA, Obradovich JE, Madewell BR, Rodriguez CO Jr, et al. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine adjuvant immunotherapy for splenic hemangiosarcoma in the dog: a randomized multi-institutional clinical trial. Clin Cancer Res. 1995 Oct;1(10):1165-70. PubMed PMID: 9815908.

37: Wang L, Roos G, Stenram U. Adverse effects at adjuvant treatment of liver metastases in rat with RSU-1069 + microspheres, or liposomal MTP-PE. Anticancer Res. 1995 Sep-Oct;15(5B):2077-80. PubMed PMID: 8572605.

38: Dieter P, Ambs P, Fitzke E, Hidaka H, Hoffmann R, Schwende H. Comparative studies of cytotoxicity and the release of TNF-alpha, nitric oxide, and eicosanoids of liver macrophages treated with lipopolysaccharide and liposome-encapsulated MTP-PE. J Immunol. 1995 Sep 1;155(5):2595-604. PubMed PMID: 7650390.

39: Thomas K, Nijenhuis AM, Dontje BH, Daemen T, Scherphof GL. Antitumor reactivity induced by liposomal MTP-PE in a liver metastasis model of colon cancer in the rat. Clin Exp Metastasis. 1995 Sep;13(5):328-36. PubMed PMID: 7641418.

40: Kleinerman ES. Biologic therapy for osteosarcoma using liposome-encapsulated muramyl tripeptide. Hematol Oncol Clin North Am. 1995 Aug;9(4):927-38. Review. PubMed PMID: 7490249.

41: Gano JB, Kleinerman ES. Liposomal MTP-PE: a promising new biologic response modifier. Oncol Nurs Forum. 1995 Jun;22(5):809-16. Review. PubMed PMID: 7675688.

42: Dinney CP, Tanguay S, Bucana CD, Eve BY, Fidler IJ. Intravesical liposomal muramyl tripeptide phosphatidylethanolamine treatment of human bladder carcinoma growing in nude mice. J Interferon Cytokine Res. 1995 Jun;15(6):585-92. PubMed PMID: 7553228.

43: Galligioni E, Favaro D, Santarosa M, Quaia M, Spada A, Freschi A, Alberti D. Induction and maintenance of monocyte cytotoxicity during treatment with liposomes containing muramyl tripeptide despite tachyphylaxis to the cytokine response. Clin Cancer Res. 1995 May;1(5):493-9. PubMed PMID: 9816008.

44: Kleinerman ES, Gano JB, Johnston DA, Benjamin RS, Jaffe N. Efficacy of liposomal muramyl tripeptide (CGP 19835A) in the treatment of relapsed osteosarcoma. Am J Clin Oncol. 1995 Apr;18(2):93-9. PubMed PMID: 7900714.

45: Kleinerman ES, Meyers PA, Raymond AK, Gano JB, Jia SF, Jaffe N. Combination therapy with ifosfamide and liposome-encapsulated muramyl tripeptide: tolerability, toxicity, and immune stimulation. J Immunother Emphasis Tumor Immunol. 1995 Apr;17(3):181-93. PubMed PMID: 7613644.

46: ten Hagen TL, van Vianen W, Bakker-Woudenberg IA. Modulation of nonspecific antimicrobial resistance of mice to Klebsiella pneumoniae septicemia by liposome-encapsulated muramyl tripeptide phosphatidylethanolamine and interferon-gamma alone or combined. J Infect Dis. 1995 Feb;171(2):385-92. PubMed PMID: 7844375.

47: Asano T, McIntyre BW, Bednarczyk JL, Wygant JN, Kleinerman ES. Liposomal muramyl tripeptide upregulates adhesion molecules on the surface of human monocytes. Oncol Res. 1995;7(5):253-7. PubMed PMID: 8534931.

48: Risin D, Kleinerman ES, Umezu Y, Pizzini RP, Balch CM, Pellis NR. Impairment of lymphocyte locomotion in the tumor microenvironment and the effect of systemic immunotherapy with liposome-encapsulated muramyl-tripeptide-phosphatidylethanolamine. Cancer Immunol Immunother. 1995 Jan;40(1):57-64. PubMed PMID: 7828168.

49: Gano JB, Kleinerman ES. Administration of liposomal MTP-PE by the local physician: the role of the research nurse. Cancer Pract. 1995 Jan-Feb;3(1):42-6. PubMed PMID: 7704060.

50: Fox LE, MacEwen EG, Kurzman ID, Dubielzig RR, Helfand SC, Vail DM, Kisseberth W, London C, Madewell BR, Rodriguez CO Jr. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine for the treatment of feline mammary adenocarcinoma--a multicenter randomized double-blind study. Cancer Biother. 1995 Summer;10(2):125-30. Erratum in: Cancer Biother 1995 Fall;10(3):249. PubMed PMID: 7663571.

51: Misúrová E, Fedorocko P. Influence of liposomal muramyl tripeptide phosphatidylethanolamine on the changes of nucleic acids in the blood and hemopoietic tissues of irradiated mice. Neoplasma. 1995;42(2):63-8. PubMed PMID: 7542365.

52: Tanguay S, Bucana CD, Wilson MR, Fidler IJ, von Eschenbach AC, Killion JJ. In vivo modulation of macrophage tumoricidal activity by oral administration of the liposome-encapsulated macrophage activator CGP 19835A. Cancer Res. 1994 Nov 15;54(22):5882-8. PubMed PMID: 7954418.

53: Kahn JO, Sinangil F, Baenziger J, Murcar N, Wynne D, Coleman RL, Steimer KS, Dekker CL, Chernoff D. Clinical and immunologic responses to human immunodeficiency virus (HIV) type 1SF2 gp120 subunit vaccine combined with MF59 adjuvant with or without muramyl tripeptide dipalmitoyl phosphatidylethanolamine in non-HIV-infected human volunteers. J Infect Dis. 1994 Nov;170(5):1288-91. PubMed PMID: 7963729.

54: Burke RL, Goldbeck C, Ng P, Stanberry L, Ott G, Van Nest G. The influence of adjuvant on the therapeutic efficacy of a recombinant genital herpes vaccine. J Infect Dis. 1994 Nov;170(5):1110-9. PubMed PMID: 7963702.

55: Galligioni E, Santarosa M, Favaro D, Spada A, Talamini R, Quaia M. In vitro synergic effect of interferon gamma combined with liposomes containing muramyl tripeptide on human monocyte cytotoxicity against fresh allogeneic and autologous tumor cells. Tumori. 1994 Oct 31;80(5):385-91. PubMed PMID: 7839471.

56: Gano JB, Kleinerman ES. Liposomal MTP-PE. J Pediatr Oncol Nurs. 1994 Oct;11(4):161-3. Review. PubMed PMID: 7946146.

57: Bui T, Dykers T, Hu SL, Faltynek CR, Ho RJ. Effect of MTP-PE liposomes and interleukin-7 on induction of antibody and cell-mediated immune responses to a recombinant HIV-envelope protein. J Acquir Immune Defic Syndr. 1994 Aug;7(8):799-806. PubMed PMID: 8021814.

58: Ding JW, Andersson R, Soltesz VL, Pärsson H, Johansson K, Wang W, Bengmark S. Inhibition of bacterial translocation in obstructive jaundice by muramyl tripeptide phosphatidylethanolamine in the rat. J Hepatol. 1994 Jun;20(6):720-8. PubMed PMID: 7930471.

59: Killion JJ, Fidler IJ. Systemic targeting of liposome-encapsulated immunomodulators to macrophages for treatment of cancer metastasis. Immunomethods. 1994 Jun;4(3):273-9. Review. PubMed PMID: 7820457.

60: van de Water B, van Berkel TJ, Kuiper J. Activation of rat Kupffer cells to tumoricidal cells by the immunomodulator muramyl tripeptide-phosphatidylethanolamine incorporated into the novel drug carrier lactosylated low density lipoprotein. Mol Pharmacol. 1994 May;45(5):971-7. PubMed PMID: 8190111.

61: Fedorocko P. Liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE) promotes haemopoietic recovery in irradiated mouse. Int J Radiat Biol. 1994 Apr;65(4):465-75. PubMed PMID: 7908934.

62: Asano T, McWatters A, An T, Matsushima K, Kleinerman ES. Liposomal muramyl tripeptide up-regulates interleukin-1 alpha, interleukin-1 beta, tumor necrosis factor-alpha, interleukin-6 and interleukin-8 gene expression in human monocytes. J Pharmacol Exp Ther. 1994 Feb;268(2):1032-9. PubMed PMID: 8113959.

63: Asano T, Matsushima K, Kleinerman ES. Liposome-encapsulated muramyl tripeptide up-regulates monocyte chemotactic and activating factor gene expression in human monocytes at the transcriptional and post-transcriptional levels. Cancer Immunol Immunother. 1994 Jan;38(1):16-22. PubMed PMID: 8299114.

64: Ho RJ, Burke RL, Merigan TC. Disposition of antigen-presenting liposomes in vivo: effect on presentation of herpes simplex virus antigen rgD. Vaccine. 1994;12(3):235-42. PubMed PMID: 8165856.

65: Melissen PM, van Vianen W, Bakker-Woudenberg IA. Treatment of Klebsiella pneumoniae septicemia in normal and leukopenic mice by liposome-encapsulated muramyl tripeptide phosphatidylethanolamide. Antimicrob Agents Chemother. 1994 Jan;38(1):147-50. PubMed PMID: 8141571; PubMed Central PMCID: PMC284413.

66: Verweij J, Judson I, Steward W, Coleman R, Woll P, van Pottelsberghe C, van Glabbeke M, Mouridsen H. Phase II study of liposomal muramyl tripeptide phosphatidylethanolamine (MTP/PE) in advanced soft tissue sarcomas of the adult. An EORTC Soft Tissue and Bone Sarcoma Group study. Eur J Cancer. 1994;30A(6):842-3. PubMed PMID: 7917546.

67: Killion JJ, Brown DR, Wilson MR, Lloyd MM, Fidler IJ. Prevention of chemotherapy- or X-irradiation-induced monocytopenia by oral administration of lipophilic muramyl tripeptide. Oncol Res. 1994;6(8):357-64. PubMed PMID: 7894085.

68: Fox LE, King RR, Shi F, Kurzman ID, MacEwen EG, Kubilis PS. Induction of serum tumor necrosis factor-alpha and interleukin-6 activity by liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (L-MTP-PE) in normal cats. Cancer Biother. 1994 Winter;9(4):329-40. PubMed PMID: 7719380.

69: MacEwen EG, Kurzman ID, Helfand S, Vail D, London C, Kisseberth W, Rosenthal RC, Fox LE, Keller ET, Obradovich J, et al. Current studies of liposome muramyl tripeptide (CGP 19835A lipid) therapy for metastasis in spontaneous tumors: a progress review. J Drug Target. 1994;2(5):391-6. PubMed PMID: 7704483.

70: Kurzman ID, Cheng H, MacEwen EG. Effect of liposome-muramyl tripeptide combined with recombinant canine granulocyte colony-stimulating factor on canine monocyte activity. Cancer Biother. 1994 Summer;9(2):113-21. PubMed PMID: 7529085.

71: Asano T, Kleinerman ES. Liposome-encapsulated MTP-PE: a novel biologic agent for cancer therapy. J Immunother Emphasis Tumor Immunol. 1993 Nov;14(4):286-92. PubMed PMID: 8280710.

72: Asano T, Fujimaki W, McWatters A, An T, Matsushima K, Kleinerman ES. Effect of Adriamycin on liposomal muramyl tripeptide's ability to up-regulate monocyte cytokine expression. Cancer Immunol Immunother. 1993 Nov;37(6):408-11. PubMed PMID: 8242665.

73: Bezault J, Walsh C, Tarcsay L, Frost H, Liebes L, Furmanski P. Analysis of the antimetastatic effects of synthetic muramyl tripeptide (CGP 19835A) encapsulated in liposomes in combination with other immunomodulatory agents and chemotherapeutic drugs. In Vivo. 1993 Nov-Dec;7(6A):487-91. Erratum in: In Vivo. 2007 May-Jun;21(3):553. In Vivo. 2007 Nov-Dec;21(6):1172. PubMed PMID: 8193265.

74: Gay B, Cardot JM, Schnell C, van Hoogevest P, Gygax D. Comparative pharmacokinetics of free muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) and liposomal MTP-PE. J Pharm Sci. 1993 Oct;82(10):997-1001. PubMed PMID: 8254500.

75: Singh RK, Berry K, Matsushima K, Yasumoto K, Fidler IJ. Synergism between human monocyte chemotactic and activating factor and bacterial products for activation of tumoricidal properties in murine macrophages. J Immunol. 1993 Sep 1;151(5):2786-93. PubMed PMID: 8360492.

76: Kurzman ID, Shi F, MacEwen EG. In vitro and in vivo canine mononuclear cell production of tumor necrosis factor induced by muramyl peptides and lipopolysaccharide. Vet Immunol Immunopathol. 1993 Sep;38(1-2):45-56. PubMed PMID: 8256437.

77: Maeda M, Asano T, Kleinerman ES. Anti-(tumor necrosis factor) alters the response of human monocytes to liposomal muramyl tripeptide. Cancer Immunol Immunother. 1993 Aug;37(3):203-8. PubMed PMID: 8334682.

78: Seger M, Gold D, Lengy J, Pauli H, Keisari Y. The schistosomulicidal activity and the production of IL-1 and TNF-alpha by peritoneal macrophages from infected mice and their potentiation by muramyl tripeptide-phosphatidyl ethanolamine (MTP-PE) treatment. Parasite Immunol. 1993 Jun;15(6):339-47. PubMed PMID: 8361776.

79: Hoedemakers RM, Vossebeld PJ, Daemen T, Scherphof GL. Functional characteristics of the rat liver macrophage population after a single intravenous injection of liposome-encapsulated muramyl peptides. J Immunother Emphasis Tumor Immunol. 1993 May 4;13(4):252-60. PubMed PMID: 8334109.

80: Teske E, Rutteman GR. Liposome-enhanced tumour therapy in canine mammary gland tumours. Tijdschr Diergeneeskd. 1993 Mar;118 Suppl 1:32S-33S. Review. PubMed PMID: 8480312.

81: Fujimaki W, Griffin JR, Kleinerman ES. Effect of ibuprofen on monocyte activation by liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (CGP 19835A): can ibuprofen reduce fever and chills without compromising immune stimulation? Cancer Immunol Immunother. 1993;36(1):45-51. PubMed PMID: 8422667.

82: Melissen PM, van Vianen W, Bidjai O, van Marion M, Bakker-Woudenberg IA. Free versus liposome-encapsulated muramyl tripeptide phosphatidylethanolamide (MTPPE) and interferon-y (IFN-y) in experimental infection with Listeria monocytogenes. Biotherapy. 1993;6(2):113-24. PubMed PMID: 8398570.

83: Macková NO, Fedorocko P. Pre- and postirradiation hemopoietic effects of liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE) administered to C57Bl/6 mice before irradiation. Neoplasma. 1993;40(6):379-85. PubMed PMID: 8289971.

84: Keitel W, Couch R, Bond N, Adair S, Van Nest G, Dekker C. Pilot evaluation of influenza virus vaccine (IVV) combined with adjuvant. Vaccine. 1993;11(9):909-13. PubMed PMID: 8212835.

85: Kleinerman ES, Maeda M, Jaffe N. Liposome-encapsulated muramyl tripeptide: a new biologic response modifier for the treatment of osteosarcoma. Cancer Treat Res. 1993;62:101-7. Review. PubMed PMID: 8096724.

86: Melissen PM, van Vianen W, Leenen PJ, Bakker-Woudenberg IA. Tissue distribution and cellular distribution of liposomes encapsulating muramyltripeptide phosphatidyl ethanolamide. Tissue and cellular distribution of LE-MTPPE. Biotherapy. 1993;7(1):71-8. Erratum in: Biotherapy 1994;8(1):85. PubMed PMID: 8068486.

87: Landmann R, Obrist R, Denz H, Ludwig C, Frost H, Wesp M, Rordorf C, Towbin H, Gygax D, Tarcsay L, et al. Pharmacokinetics and immunomodulatory effects on monocytes during prolonged therapy with liposomal muramyltripeptide. Biotherapy. 1993;7(1):1-12. PubMed PMID: 8068481.

88: Fujimaki W, Itoh K, An T, Gano JB, Ross MI, Mansfield PF, Balch CM, Augustus LB, Karkevitch DD, Johnston D, et al. Cytokine production and immune cell activation in melanoma patients treated with liposomal muramyl tripeptide (CGP 19835A lipid). Cancer Biother. 1993 Winter;8(4):307-18. PubMed PMID: 7804372.

89: Smith BW, Kurzman ID, Schultz KT, Czuprynski CJ, MacEwen EG. Muramyl peptides augment the in vitro and in vivo cytostatic activity of canine plastic-adherent mononuclear cells against canine osteosarcoma cells. Cancer Biother. 1993 Summer;8(2):137-44. PubMed PMID: 7804354.

90: Asao T, Shibata HR, Batist G, Brodt P. Eradication of hepatic metastases of carcinoma H-59 by combination chemoimmunotherapy with liposomal muramyl tripeptide, 5-fluorouracil, and leucovorin. Cancer Res. 1992 Nov 15;52(22):6254-7. PubMed PMID: 1423270.

91: Ullrich SE, Fidler IJ. Liposomes containing muramyl tripeptide phosphatidylethanolamine (MTP-PE) are excellent adjuvants for induction of an immune response to protein and tumor antigens. J Leukoc Biol. 1992 Nov;52(5):489-94. PubMed PMID: 1431559.

92: Melissen PM, van Vianen W, Bakker-Woudenberg IA. Roles of peripheral leukocytes and tissue macrophages in antibacterial resistance induced by free or liposome-encapsulated muramyl tripeptide phosphatidylethanolamide. Infect Immun. 1992 Nov;60(11):4891-7. PubMed PMID: 1399000; PubMed Central PMCID: PMC258245.

93: Kleinerman ES, Jia SF, Griffin J, Seibel NL, Benjamin RS, Jaffe N. Phase II study of liposomal muramyl tripeptide in osteosarcoma: the cytokine cascade and monocyte activation following administration. J Clin Oncol. 1992 Aug;10(8):1310-6. PubMed PMID: 1634921.

94: Picci P. Osteosarcoma and other cancers of bone. Curr Opin Oncol. 1992 Aug;4(4):674-80. Review. PubMed PMID: 1511023.

95: Seger M, Gold D, Lengy J, Pauli H, Keisari Y. On the interaction between macrophages and developmental stages of Schistosoma mansoni: effect of muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) treatment on mice survival and the generation of schistosomulicidal macrophages. Parasite Immunol. 1992 Jul;14(4):355-69. PubMed PMID: 1437229.

96: de Vries EG, Mulder NH, Daemen T. Current state of liposome-complexed drugs in the treatment of cancer patients. Ann Oncol. 1992 Jun;3(6):419-21. PubMed PMID: 1498057.

97: Liebes L, Walsh CM, Chachoua A, Oratz R, Richards D, Hochster H, Peace D, Marino D, Alba S, Le Sher D, et al. Modulation of monocyte functions by muramyl tripeptide phosphatidylethanolamine in a phase II study in patients with metastatic melanoma. J Natl Cancer Inst. 1992 May 6;84(9):694-9. PubMed PMID: 1569602.

98: Ziegler-Heitbrock HW, Passlick B, Käfferlein E, Coulie PG, Izbicki JR. Protection against lethal pneumococcal septicemia in pigs is associated with decreased levels of interleukin-6 in blood. Infect Immun. 1992 Apr;60(4):1692-4. PubMed PMID: 1548092; PubMed Central PMCID: PMC257049.

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