Abstract
Liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) is a biological agent in phase I and II trials for osteosarcoma and melanoma. Its mechanism of action has been linked to its ability to activate monocyte tumoricidal function and to stimulate monocyte production of tumor necrosis factor (TNF) and interleukins(IL)-1, −6, and −8. Our ultimate goal is to combine L-MTP-PE with chemotherapy. The purpose of this study was to determine whether doxorubicin (Adriamycin) interfered with the ability of L-MTP-PE to activate monocyte cytokine production. Human monocytes were cultured with or without 5–500 ng/ml of Adriamycin for 3 h and washed before being exposed to 2 μg/ml L-MTP-PE for 16 h. Cultured supernatants were collected and assayed for TNF, IL-1, IL-6, and IL-8. The messenger RNA expression of IL-1α, IL-1β, TNFα, IL-6, and IL-8 was quantified with northern blot analysis. Adriamycin did not suppress the upregulation of any of these cytokines. We concluded that combination therapy with L-MTP-PE and Adriamycin is feasible and that this combination warrents further investigation in a clinical setting.
References
Alexander RB, Nelson WG, Coffey DS (1987) Synergistic enhancement by tumor necrosis factor of in vitro cytotoxicity from chemotherapeutic drugs targeted at DNA topoisomerase II. Cancer Res 47:2403
Arinaga S, Akiyoshi T, Tsuji H (1986) Augmentation of the generation of cell-mediated cytotoxicity after a single dose of Adriamycin in cancer patients. Cancer Res 46:4213
Cohen SA, Ehrke MJ, Ryoyama K, Mihich E (1982) Augmentation of the phagocytic activity of murine spleen cell populations induced by Adriamycin. Immunopharmacology 5:75
Ehrke MJ, Ryoyama K, Cohen SA (1984) Cellular basis for Adriamycin-induced augmentation of cell-mediated cytotoxicity in culture. Cancer Res 44:2497
Fidler IJ, Sone S, Fogler WE, Barnes ZL (1981) Eradication of spontaneous metastasis and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc Natl Acad Sci USA 78:1680
Giavazzi R, Bucana CD, Hart IR (1984) Correlation of tumor growth inhibitory activity of macrophages exposed to Adriamycin and Adriamycin sensitivity of the target tumor cells. J Natl Cancer Inst 73:447
Goldie JH, Coldman AJ (1979) A mathematical model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Res 63:1727
Hudson MM, Snyder JS, Jaffe N, Kleinerman ES (1988) In vitro and in vivo effect of Adriamycin therapy on monocyte activation by liposome-encapsulated immunomodulators. Cancer Res 48:5256
Killion JJ, Kleinerman ES, Wilson MR, Tanaka M, Fidler IJ (1992) Sequential therapy with chemotherapeutic drugs and liposome-encapsulated muramyl tripeptide: determination of potential interactions between these agents. Oncology Res 4:413
Kleinerman ES, Erickson KL, Schroit AJ, Fogler WE, Fidler IJ (1983) Activation of tumoricidal properties in human blood monocytes by liposomes containing muramyl lipophilic tripeptide. Cancer Res 43:2010
Kleinerman MS, Jia S-F, Griffin J, Seibel NL, Benjamin RS, Jaffe N (1992) Phase II study of liposomal muramyl tripeptide in osteosarcoma: the cytokine cascade and monocyte activation following administration. J Clin Oncol 10:1310
Maccubbin DL, Wing KR, Mace KF, Ho RLX, Ehrke MJ, Mihich E (1992) Adriamycin-induced moduation of host-defenses in tumor-bearing mice. Cancer Res 52:3572
MacEwen EG, Kurzman ID, Rosenthal RC, Smith BW, Manley PA, Roush JK, Fidler IJ (1989) Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. J Natl Cancer Inst 81:935
Maeda M, Knowles RD, Kleinerman ES (1991) Muramyl tripeptide phosphatidylethanolamine (MTP-PE) encapsulated in liposomes stimulates monocyte production of tumor necrosis factor and interleukin-1 in vivo. Cancer Commun 3:313
Mantovani A, Vecchi A (1990) Interactions of cancer chemotherapy agents with the mononuclear phagocyte system. Prog Drug Res 35:487
Melton DA, Krieg PA, Rebagliati MR, Maniatis T, Zinn K, Green MR (1984) Effecient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res 12:7035
Murray JL, Kleinerman ES, Cunningham JE, Tatom JR, Andrejcio K, Lepe-Zuniga J, Lamiki LM, Rosenblum MG, Frost H, Gutterman JH, Fidler IJ, Krakoff IH (1989) Phase I trial of liposomal muramyl tripeptide phophatidylethanolamine in cancer patients. J Clin Oncol 7:1915
Orsini F, Pavelic Z, Mihich E (1977) Increased primary cell mediated immunity in culture subsequent to Adriamycin or daunorabicin treatment of spleen donor mice. Cancer Res 37:1719
Poste G, Bucana C, Raz A, Bugelski P, Kirsh R, Fidler IJ (1982) Analysis of the fate of systemically administered liposomes and implications for their use in drug delivery. Cancer Res 42:1412
Riccardi C, Puccetti P, Santoni A, Herberman RB, Bonmassar E (1979) Adriamycin-induced antitumor response in lethally irradiated mice. Immunopharmacology 1:211
Santoni A, Riccardi C, Sorci V, Herberman RB (1980) Effects of Adriamycin on the activity of mouse natural killer cells. J Immunol 124:2329
Schroit AJ, Fidler IJ (1982) Effect of liposome structure and lipid composition on the activation of the tumoricidal properties of macrophages by liposomes containing muramyl dipeptide. Cancer Res 42:161
Tomazic V, Ehrke MJ, Mihich E (1980) Modulation of the cytotoxic response against allogeneic tumor cells in culture by Adriamycin. Cancer Res 40:2748
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Asano, T., Fujimaki, W., McWatters, A. et al. Effect of Adriamycin on liposomal muramyl tripeptide's ability to up-regulate monocyte cytokine expression. Cancer Immunol Immunother 37, 408–411 (1993). https://doi.org/10.1007/BF01526798
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DOI: https://doi.org/10.1007/BF01526798