Abstract
The uncontrolled growth of metastases resistant to conventional therapeutic modalities is a major cause of death from cancer. Data from our laboratory and others indicate that metastases arise from the nonrandom spread of specialized malignant cells that preexist within a primary neoplasm. These metastases can be clonal in their origin, and different metastases can originate from different progenitor cells. In addition, metastatic cells can exhibit an increased rate of spontaneous mutation compared with benign nonmetastatic cells. These data provide an explanation for the clinical observation that multiple metastases can exhibit different sensitivities to the same therapeutic modalities. These findings suggest that the successful therapy of disseminated metastases will have to circumvent the problems of neoplastic heterogeneity and the development of resistance.
Appropriately activated macrophages can fulfill these demanding criteria. Macrophages can be activated to become tumoricidal by interaction with phospholipid vesicles (liposomes) containing immunomodulators. Tumoricidal macrophages can recognize and destroy neoplastic cells in vitro and in vivo, leaving non-neoplastic cells uninjured. Although the exact mechanism(s) by which macrophages discriminate between tumorigenic and normal cells is unknown, it is independent of tumor cell characteristics such as immunogenicity, metastatic potential, and sensitivity to cytotoxic drugs. Moreover, macrophage destruction of tumor cells apparently is not associated with the development of tumor cell resistance.
Macrophages are found in association with malignant tumors in a definable pattern, suggesting that the most direct way to achieve macrophage-mediated tumor regression is in situ macrophage activation. Intravenously administered liposomes are cleared from the circulation by phagocytic cells, including macrophages, so when liposomes containing immunomodulators are endocytosed, cytotoxic macrophages are generated in situ. The administration of such liposomes in certain protocols has been shown to bring about eradication of cancer metastases.
Macrophage destruction of metastases in vivo is significant, provided that the total tumor burden at the tart of treatment is minimal. For this reason, we have been investigating various methods to achieve maximal cytoreduction in metastases by modalities such as chemotherapy or radiotherapy prior to macrophage-directed therapy. It is important to note that even the destruction of 99.9% of cells in a metastasis measuring 1 cm2 would leave 106 cells to proliferate and kill the host. The ability of tumoricidal macrophages to distinguish neoplastic from bystander nonneoplastic cells presents an attractive possibility for treatment of the few tumor cells which escape destruction by conventional treatments.
Macrophage-directed therapy has been studied in several human protocols, yielding important biological information about the use of liposome-encapsulated macrophage activators in cancer patients. Currently, Phase II and Phase JB protocols are being conducted based on the results from Phase I trials.
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References
Fidler IJ, Gersten DM, Hart IR: The biology of cancer invasion and metastasis. Adv Cancer Res 28: 149–259, 1978
Poste G, Fidler IJ: The pathogenesis of cancer metastasis. Nature 283: 139–146, 1979
Fidler IJ, Balch CM: The biology of cancer metastasis and implications for therapy. Curr Probl Surg 24: 131–209, 1987
Fidler IJ, Poste G: The cellular heterogeneity of malignant neoplasms: implications for adjuvant chemotherapy. Semin Oncol 12: 207–222, 1985
Nicolson GL: Tumor cell instability, diversification and progression to the metastatic phenotype: From oncogenes to oncofetal expression. Cancer Res 47: 1473–1488, 1987
Fidler IJ, Kripke ML: Metastasis results from preexisting variant cells within a malignant tumor. Science 197: 893–895, 1977
Talmadge JE, Wolman SR, Fidler IJ: Evidence for the clonal origin of spontaneous metastases. Science 217: 361–363, 1982
Hu F, Wang RY, Hsu TC: Clonal origin of metastasis in B-16 murine melanoma: A cytogenetic study. J Natl Cancer Inst 78: 153–163, 1987
Talmadge JE, Zbar B: Clonality of pulmonary metastases from the bladder 6 subline of the B16 melanoma studied by Southern hybridization. J Natl Cancer Inst 78: 315–320, 1986
Kerbel RS, Waghorne C, Man MS, Elliot B, Breitman ML: Alteration of the tumorigenic and metastatic properties of neoplastic cells is associated with the process of calcium phosphate-mediated DNA transfection. Proc Natl Acad Sci USA 84: 1263–1267, 1987
Fidler IJ, Talmadge JE: Evidence that intravenously derived murine pulmonary melanoma metastases can originate from the expansion of a single tumor cell. Cancer Res 46: 5167–5171, 1986
Cifone MA, Fidler IJ: Correlation of patterns of anchorage-independent growth with in vivo behavior of cells from a murine fibrosarcoma. Proc Natl Acad Sci USA 77: 1039–1043, 1980
Fidler IJ: Macrophages and metastasis—a biological approach to cancer therapy: Presidential address. Cancer Res 45: 4714–4726, 1985
Fidler IJ, Schroit AJ: Recognition and destruction of neoplastic cells by activated macrophages: Discrimination of altered self. Biochim Biophys Acta 948: 151–173, 1988
Takahashi K, Takahashi H, Naito M, Sato T, Kojima M: Ultrastructural and functional development of macrophages in the dermal tissue of rat fetuses. Cell Tissue Res (232): 539–552, 1983
Calandra AJ, MacCabe JA: The in vitro maintenance of the limb-bud apical ridge by cell-free preparations. Dev Biol 62: 258–269, 1978
Salzmann R, Weber R: Histochemical localization of acid phosphatase and cathepsin-like activities in regressing tails of Xenopus larvac at metamorphosis. Experientia 19: 352–354, 1963
Derby A, McEldoon W: Changes in the tail of Ambystoma maculatum at different stages of metamorphosis: Observations on tissue remodeling and its relationship to hydrolytic enzymes. J Exp Zool 196: 205–214, 1976
Zeira M, Gallily R: Interaction between thymocytes and thymus-derived macrophages. I. Surface components participating in mutual recognition. Cellular Immunol 117: 264–276, 1988
Zeira M, Gallity R: Interaction between thymocytes and thymus-derived macrophages. II. Engulfment of thymocytes by macrophages. Cell Immunol 117: 277–288, 1988
Bessis MC, Breton-Gorius J: Iron metabolism in the bone marrow as seen by electron microscopy: A critical review. Blood 19: 635–663, 1962
Hume DA, Robinson AP, MacPherson GG, Gordon S: The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80. J Exp Med 158: 1522–1536, 1983
Bagby GC: Production of multilineage growth factors by hematopoietic stromal cells: An intercellular regulatory network involving mononuclear phagocytes and interleukin-1. Blood Cells 13: 147–159, 1987
Bessis M, Mize C, Prenant M: Erythropoiesis: Comparison of in vivo and in vitro amplification. Blood Cells 4: 155–174, 1978
Blasi E, Back TC, Stull SW, Varesio L: Regulation of bone marrow cell survival in short-term cultures: A new macrophage function. Cell Immunol 104: 334–342, 1987
Murphy M, Perussia B, Trinchieri G: Effects of recombinant tumor necrosis factor, lymphotoxin, and immune interferon on proliferation and differentiation of enriched hematopoietic precursor cells. Exp Hematol 16: 131–138, 1988
Pennathur-Das R, Levitt L: Augmentation of in vitro human marrow crythropoiesis under physiological oxygen tensions is mediated by monocytes and T lymphocytes. Blood 69: 899–907, 1987
Rinehart JJ, Zanhani ED, Nomdedeu B, Gormus BJ, Kaplan ME: Cell-cell interaction in erythropoiesis. J Clin Invest 62: 979–986, 1978
Crocker PR, Gordon S: Isolation and characterization of resident stromal macrophages and hematopoietic cell clusters from mouse bone marrow. J Exp Med 162: 993–1014, 1985
Morris L, Crocker PR, Gordon S: Murine fetal liver macrophages bind developing erythroblasts by a divalent cation-dependent hemagglutinin. J Cell Biol 106: 649–656, 1988
McCurdy PR: 32-DFP and 51Cr for measurement of red cell life span in abnormal hemoglobin syndromes. Blood 33: 214–224, 1969
Danon D, Marikovsky Y, Skutelsky E: The sequestration of old red cells and extruded erythroid nuclei. In: Ramob B (ed) Red Blood Cell Structure and Metabolism. Academic Press, New York, 1971, pp 23–28
Bocci V: The role of sialic acid in determining the life-span of circulating cells and glycoproteins. Experientia 32: 135–140, 1976
Kay MM: Mechanism of removal of senescent cells by human macrophages in situ. Proc Natl Acad Sci USA 72: 3521–3525, 1975
Kay MM: Cells, signals, and receptors: The role of physiological autoantibodies in maintaining homeostasis. Adv Exp Med Biol 129: 171–200, 1980
Alderman EM, Fudenberg HH, Lovins RE: Isolation and characterization of an age-related antigen present on senescent human red blood cells. Blood 58: 341–349, 1981
Low PS, Waugh SM, Zinke K, Drenckhahn D: The role of hemoglobin denaturation and band 3 clustering in red blood cell aging. Science 227: 532–533, 1985
Gordesky SE, Marinetti GV: The asymetric arrangement of phospholipids in the human erythrocyte membrane. Biochem Biophys Res Commun 50: 1027–1031, 1973
Verkleij AJ, Zwaal RF, Roelofsen B, Comfurius P, Kastelijn D, van Deenen LL: The asymmetric distribution of phospholipids in the human red cell membrane. A combined study using phospholipases and freeze-etch electron microscopy. Biochem Biophys Acta 323: 178–193, 1973
Rothman JE, Lenard J: Membrane symmetry. Science 195: 743–753, 1977
Chiu D, Lubin B, Shohet SB: Erythrocyte membrane lipid reorganization during the sickling process. Br J Haematol 41: 223–234, 1979
Op den Kamp JA: Lipid asymmetry in membranes. Annu Rev Biochem 48: 47–71, 1979
Zwaal FA, Bevers EM: Structural and functional aspects of the platelet plasma membrane. In: Op den Kamp JAF, Roelofsen B, Wirtz KWA (eds) Lipids and Membranes: Past, Present and Future. Elsevier Science Publishers, Amsterdam, 1986, pp 231–257
Milton JG, Frojmovic MM, Tang SS, White JG: Spontaneous platelet aggregation in a hereditary giant platelet syndrome (MPS). Am J Pathol 114: 336–345, 1984
Fontaine RN, Schroeder F: Plasma membrane aminophospholipid distribution in transformed murine fibroblasts. Biochim Biophys Acta 558: 1–12, 1979
Record M, El-Tamer A, Chap H, Douste-Blazy L: Evidence for a highly asymmetric arrangement of ether- and diacyl-phospholipid subclasses in the plasma membrane of Krebs II ascites cells. Biochim Biophys Acta 778: 449–456, 1984
VanderSchaft PH, Roelofsen B, Op den Kamp JA, Van Deenan LL: Phospholipid asymmetry during erythropoiesis. A study on Friend erythroleukemic cells and mouse reticulocytes. Biochim Biophys Acta 900: 103–115, 1987
Tanaka Y, Schroit AJ: Insertion of fluorescent phosphatidylserine into the plasma membrane of red blood cells. Recognition by autologous macrophages. J Biol Chem 258: 11335–11343, 1983
Schwartz RS, Tanaka Y, Fidler IJ, Chiu DT, Lubin B, Schroit AJ: Increased adherence of sickled and phosphatidylserine-enriched human erythrocytes to cultured human peripheral blood monocytes. J Clin Invest 75: 1965–1972, 1985
Schroit AJ, Tanaka Y, Madsen J, Fidler IJ: The recognition of red blood cells by macrophages: Role of phosphatidylserine and possible implications of membrane phospholipid asymmetry. Biol Cell 51: 227–238, 1984
Schroit AJ, Madsen JW, Tanaka Y: In vivo recognition and clearance of red blood cells containing phosphatidylserine in their plasma membranes. J Biol Chem 260: 5131–5138, 1985
Chiu D, Lubin B, Shohet SB: Erythrocyte membrane lipid reorganization during the sickling process. Br J Haematol 41: 223–234, 1979
Lubin B, Chiu D, Bastacky J, Roelofsen B, Van Deenen LL: Abnormalities in membrane phospholipid organization in sickled erythrocytes. J Clin Invest 67: 1643–1649, 1981
Schwartz RS, Tanaka Y, Fidler IJ, Chiu DT, Lubin B, Schroit AJ: Increased adherence of sickled and phosphatidylserine-enriched human erythrocytes to cultured human peripheral blood monocytes. J Clin Invest 75: 1965–1972, 1985
Ratner S, Schroit AJ, Vinson SB, Fidler IJ: Analogous recognition of phospholipids by insect phagocytes and mammalian macrophages. Proc Soc Exp Biol Med 182: 272–276, 1986
Marks PA, Rifkind RA: Erythroleukemic differentiation. Annu Rev Biochem 47: 419–448, 1978
Reuben RC, Wife RL, Breslow R, Rifkind RA, Marks PA: A new group of potent inducers of differentiation in murine erythroleukemia cells. Proc Natl Acad Sci USA 73: 862–866, 1976
Pak CC, Fidler IJ: Activated macrophages distinguish undifferentiated-tumorigenic from differentiated-nontumorigenic murine erythroleukemia cells. Differentiation 41: 49–55, 1989
Connor J, Bucana C, Fidler IJ, Schroit AJ: Differentiation-dependent expression of phosphatidylserine in mammalian plasma membranes: Quantitative assessment of outer leaflet lipid by prothrombinase complex formation. Proc Natl Acad Sci USA 86: 3184–3188, 1989
Fidler IJ, Kleinerman ES: Lymphokine-activated human blood monocytes destroy tumor cells but not normal cells under cocultivation conditions. J Clin Oncol 2: 937–943, 1984
Shimizu H, Wyatt D, Knowles RD, Bucana CD, Stanbridge EJ, Kleinerman ES: Human monocytes selectively bind to cells expressing the tumorigenic phenotype. Cancer Immunol Immunother 28: 185–192, 1989
Bucana CD, Hoyer LC, Schroit AJ, Kleinerman ES, Fidler IJ: Ultrastructural studies of the interaction between liposome-activated human blood monocytes and allogeneic tumor cells in vitro. Am J Pathol 112: 101–111, 1983
Fidler IJ: Recognition and destruction of target cells by tumoricidal macrophages. Isr J Med Sci 14: 177–191, 1978
Fidler IJ, Roblin RO, Poste G: In vitro tumoricidal activity of macrophages against virus-transformed lines with temperature-dependent transformed phenotypic characteristics. Cell Immunol 38: 131–146, 1978
Fidler IJ, Cifone MA: Properties of metastatic and nonmetastatic cloned subpopulations of an ultraviolet-light-induced murine fibrosarcoma of recent origin. Am J Pathol 97: 633–648, 1979
Miner KM, Nicolson GL: Differences in the sensitivities of murine metastatic lymphoma/lymphosarcoma variants to macrophage-mediated cytolysis and/or cytostasis. Cancer Res 43: 2063–2067, 1983
Miner KM, Klostergaard J, Granger GA, Nicolson GL: Differences in cytotoxic effects of activated murine peritoneal macrophages and J774 monocytic cells on metastatic variants of B16 melanoma. J Natl Cancer Inst 70: 717–724, 1983
Nowell PC: The clonal evolution of tumor cell populations. Science 194: 23–28, 1976
Wolman SR, McMorrow LE, Fidler IJ, Talmadge JE: Development and progression of karyotypic variability in melanoma K1735 following X-irradiation. Cancer Res 45: 1839–1844, 1985
Giavazzi R, Scholar E, Hart IR: Isolation and preliminary characterization of an Adriamycin-resistant murine fibrosarcoma cell line. Cancer Res 43: 2216–2222, 1983
Giavazzi R, Bucana CD, Hart IR: Correlation of tumor growth inhibitory activity of macrophages exposed to Adriamycin and Adriamycin-sensitivity of the target tumor cells. J Natl Cancer Inst 73: 447–455, 1984
Hibbs JBJr: Discrimination between neoplastic and nonneoplastic cells in vitro activated macrophages. J Natl Cancer Inst 53: 1487–1492, 1974
Hibbs JBJr, Lambert LH, Remington JS: Control of carcinogenesis: A possible role for the activated macrophage. Science 177: 998–1000, 1972
Norbury KC, Kripke ML: Ultraviolet-induced carcinogenesis in mice treated with silica, trypan blue or pyran copolymer. J Reticuloendothel Soc 26: 827–837, 1979
Jones PDE, Castro JE: Immunological mechanism in metastatic spread and the antimetastatic effects of C. parvum. Br J Cancer 35: 519–527, 1977
Sadler TE, Jones DDE, Castro JE: The effects of altered phagocytic activity on growth of primary and metastatic tumors. In: McBride JF, Stuart A (eds) The Macrophage and Cancer. Econoprint, Edinburgh, 1979, pp 115–163
Mantovani A, Giavazzi R, Polentanitti N, Spreafico F, Garattini S: Divergent effects of macrophage toxins on growth of primary tumors and lung metastases in mice. Int J Cancer 25: 617–624, 1980
Fidler IJ: Inhibition of pulmonary metastasis by intravenous injection of specifically activated macrophages. Cancer Res 34: 1074–1078, 1974
Liotta LA, Gattozzi C, Kleinerman J: Reduction of tumor cell entry into vessels by BCG-activated macrophages. Br J Cancer 36: 639–641, 1977
Den Otter W, Dullens Hub JJ, Can Lovern H, Pels E: Anti-tumor effects of macrophages injected into animals: A review. In: James K, McBride B, Stuart A (eds) The Macrophage and Cancer. Econoprint, Edinburgh, 1977, pp 119–141
Normann SJ: Macrophage infiltration and tumor progression. Cancer Metastasis Rev 4: 277–291, 1985
Bugelski PJ, Kirsh RL, Sowinski JM, Poste G: Changes in the macrophage content of lung metastases at different stages in tumor growth. Am J Pathol 118: 419–424, 1985
Bugelski PJ, Kirsh R, Poste G: New histochemical method for measuring intratumoral macrophages and macrophage recruitment into experimental metastases. Cancer Res 43: 5493–5501, 1983
Bugelski PJ, Corwin S, Kirsh R, Poste G: Effect of the primary tumor on the macrophage content of its metastases. Proc Am Assoc Cancer Res 25: 265, 1984
Normann SJ, Schardt MC, Sorkin E: Macrophage inflammatory responses in rats and mice with autochthonous and transplanted tumors induced by 3-methylcholanthrene. J Natl Cancer Inst 72: 175–184, 1984
Normann SJ, Schardt M, Sorkin E: Anti-inflammatory effect of spontaneous lymphoma in SJL/J mice. J Natl Cancer Inst 63: 825–833, 1979
Normann SJ, Schardt M, Sorkin E: Alteration of macrophage function in AKR leukemia. J Natl Cancer Inst 66: 157–162, 1981
Bernstein ID, Zbar B, Rapp HJ: Impaired inflammatory response in tumor-bearing guinea pigs. J Natl Cancer Inst 49: 1641–1647, 1972
Fauve RM, Hevin B, Jacob H, Gaillard JA, Jacob F: Anti-inflammatory effects of murine malignant cells. Proc Natl Acad Sci USA 71: 4052–4056, 1974
Snyderman R, Pike MC, Blaylock BL, Weinstein P: Effect of neoplasms on inflammation: Depression of macrophage accumulation after tumor implantation. J Immunol 116: 585–589, 1976
Normann SJ, Sorkin E: Cell-specific defect in monocyte function during tumor growth. J Natl Cancer Inst 57: 135–140, 1976
Bugelski PJ, Corwin SP, North SM, Kirsh RL, Nicolson GL, Poste G: Macrophage content of spontaneous metastases at different stages of growth. Cancer Res 47: 4141–4145, 1987
Bugelski PJ, Kirsh R, Buscarino C, Corwin SP, Poste G: Recruitment of exogenous macrophages into metastases at different stages of tumor growth. Cancer Immunol Immunother 24: 93–98, 1987
Kalish R, Jones V: Role of activated macrophages and antibody in inhibition and enhancement of tumor growth in rats. Lancet II: 847, 1971
Schackert G, Simmons RD, Buzbee TM, Hume DA, Fidler IJ: Macrophage infiltration into experimental brain metastasis occurs through an intact blood-brain barrier. J Natl Cancer Inst 80: 1027–1035, 1988
Talmadge JE, Key M, Fidler IJ: Macrophage content of metastatic and nonmetastatic rodent neoplasms. J Immunol 126: 2245–2248, 1981
Pross HF, Kerbel RS: An assessment of intratumor phagocytic and surface marker-bearing cells in a series of authochthonous and early passaged chemically induced murine sarcomas. J Natl Cancer Inst 57: 1157–1167, 1976
Fidler IJ, Raz A: The induction of tumoricidal capacities in mouse and rat macrophages by lymphokines. In: Pick E (ed) Lymphokines. Academic Press, New York, 1981, pp 345–363
Allison AC: On the role of mononuclear phagocytes in immunity against viruses. Prog Med Virol 18: 15–31, 1974
Allison AC: Mode of action of immunological adjuvants. J Reticuloendothel Soc 26: 619–630, 1979
Chedid L, Audibert F, Johnson AG: Biological activities of muramyl dipeptide, a synthetic glycopeptide analogous to bacterial immunoregulating agents. Prog Allergy 25: 63–80, 1978
Lederer E: Synthetic immunostimulants derived from the bacterial cell wall. J Med Chem 23: 819–825, 1980
Fogler WE, Fidler IJ: Modulation of the immune response by muramyl dipeptide. In: Chirigos MA, Fenichel RL (eds) Immune Modulation Agents and Their Mechanisms. Marcel Dekker, New York, 1984, pp 499–512
Gisler RH, Dietrich FM, Baschang G, Brownbill A, Schumann G, Staber FB, Tarcsay L, Wachsmuth ED, Dukor P: New developments in drugs enhancing the immune response: Activation of lymphocytes and accessory cells by muramyl peptides. In: Turk JL, Danker D (eds) Immune Responsiveness. MacMillan, London, 1979, pp 133–160
Parant M, Parant F, Chedid L, Yapo A, Petit JF, Lederer E: Fate of the synthetic immunoadjuvant muramyl dipeptide in the mouse. Int J Immunopharmacol 1: 35–41, 1979
Fogler WE, Wade R, Brundish DE, Fidler IJ: Distribution and fate of free and liposome-encapsulated [3H]muramyl tripeptide phosphatidylethanolamine in mice. J Immunol 135: 1372–1377, 1985
Fidler IJ, Fogler WE, Tarcsay L, Schumann G, Braun DG, Schroit AJ: Systemic activation of macrophages and treatment of cancer metastases by liposomes containing hydrophilic or lipophilic muramyl dipeptide. Immunopharmacol 2: 253–353, 1983
Kleinerman ES, Fidler IJ: Production and utilization of human lymphokines containing macrophage-activating factor (MAF) activity. Lymphokine Res 2: 7–12, 1983
Kleinerman ES, Schroit AJ, Fogler WE, Fidler IJ: Tumoricidal activity of human monocytes activated in vitro by free and liposome-encapsulated human lymphokines. J Clin Invest 72: 1–12, 1983
Saiki I, Fidler IJ: Synergistic activation by recombinant mouse interferon-gamma and muramyl dipeptide of tumoricidal properties in mouse macrophages. J Immunol 135: 684–688, 1985
Saiki I, Sone S, Fogler WE, Kleinerman ES, Lopez-Berestein G, Fidler IJ: Synergism between human recombinant gamma-interferon and muramyl dipeptide encapsulated in liposomes for activation of antitumor properties in human blood monocytes. Cancer Res 45: 6188–6193, 1985
Fidler IJ, Fogler WE, Kleinerman ES, Saiki I: Abrogation of species specificity for activation of tumoricidal properties in macrophages by recombinant mouse or human gamma interferon encapsulated in liposomes. J Immunol 135: 4289–4294, 1985
Kleinerman ES, Fogler WE, Fidler IJ: Intracellular activation of human and rodent macrophages by human lymphokines encapsulated in liposomes. J Leukocyte Biol 37: 571–584, 1985
Poste G, Kirsh R, Fogler WE, Fidler IJ: Activation of tumoricidal properties in mouse macrophages by lymphokines encapsulated in liposomes. Cancer Res 39: 881–892, 1979
Hibbs JBJr: Discrimination between neoplastic and nonneoplastic cells by in vitro activated macrophages. J Natl Cancer Inst 53: 1487–1492, 1974
Bucana CD, Hoyer LL, Hobbs B, Breesman S, McDaniel M, Hanna MGJr: Morphological evidence for the translocation of lysosomal organelles from cytotoxic macrophages into the cytoplasm of tumor target cells. Cancer Res 36: 4444–4458, 1976
Fogler WE, Fidler IJ: Nonselective destruction of murine neoplastic cells by syngencic tumoricidal macrophages. Cancer Res 45: 14–18, 1985
Fidler IJ: Immunomodulation of macrophages for cancer and antiviral therapy. In: Tomlinson E, Davis SS (eds) Site-specific drug delivery. John Wiley and Sons, New York, 1986, pp 111–135
Gregoriadis G, Allison AC (eds): Liposomes in Biological Systems. Wiley Interscience, New York, 1980
Fidler IJ, Fogler WE, Connor J: (1979) The rationale for the treatment of established experimental micrometastases with the injection of tumoricidal macrophages. In: Terry WD, Yamamura Y (eds) Immunobiology and Immunotherapy of Cancer. Elsevier, New York, 1979, pp 361–375
Papermaster BW, Holtermann OA, Rosner D, Klein E, Dao T, Djerassi I: Regressions produced in breast cancer lesions by a lymphokine fraction from a human lymphoid cell line. Res Commun Pathol Pharmacol 8: 413–416, 1974
Salvin SB, Youngner JS, Nishio J, Neta R. Tumor suppression by a lymphokine released into the circulation of mice with delayed hypersensitivity. J Natl Cancer Inst 55: 1233–1236, 1975
Kleinerman ES, Kurzrock R, Wyatt D, Quesada JR, Gutterman JU, Fidler IJ: Activation or suppression of the tumoricidal properties of monocytes from cancer patients following treatment with human recombinant gamma interferon. Cancer Res 46: 5401–5405, 1986
Poste G, Kirsh R, Fidler IJ: Rapid decay of tumoridical activity and loss of responsiveness to lymphokines in inflammatory macrophages. Cancer Res 39: 2582–2590, 1979
Poste G, Kirsh R, Fidler IJ: Cell surface receptors for lymphokines. Cell Immunol 44: 71–88, 1979
Kripke ML, Budmen MB, Fidler IJ: Production of specific macrophage-activating factor by lymphocytes from tumor-bearing mice. Cell Immunol 30: 341–348, 1976
Fidler IJ, Jessup JM, Fogler WE, Staerkel R, Mazumder A: Activation of tumoricidal properties in peripheral blood monocytes of patients with colorectal carcinoma. Cancer Res 44: 994–998, 1986
Gregoriadis G (ed): Liposomes as Drug Carriers: Recent Trends and Progress. John Wiley and Sons, New York, 1988
Ostro MJ: Liposomes. Sci Am 256: 102–111, 1988
Hwang KJ: Liposome pharmacokinetics. In: Ostro MJ (ed) Liposomes from Biophysics to Therapeutics. Marcel Dekker, New York, 1987, pp 109–156
Alving CR: Delivery of liposome-encapsulated drugs to macrophages. Pharmacol Ther 22: 407–424, 1983
Poste G, Kirsh R, Bugelski P: Liposomes as a drug delivery system in cancer therapy. In: Sunkara P (ed) Novel Approaches to Cancer Chemotherapy. Academic Press, New York, 1984, pp 323–335
Papahadjopoulos D: Liposomes in drug delivery: From serendipity to tumor targeting. In: Lopez-Berestein G, Fidler IJ (eds) Liposomes in the Therapy of Infectious Diseases and Cancer. Alan R. Liss, Inc., New York, 1989, pp 135–155
Fidler IJ: Targeting of immunomodulators to mononuclear phagocytes for therapy of cancer. Advances in Drug Delivery Reviews 2: 69–106, 1988
Daoud SS, Hume LR, Juliano RL: Liposomes in cancer therapy. Advances in Drug Delivery Reviews 3: 405–418, 1989
Schroit AJ, Hart IR, Madsen J, Fidler IJ: Selective delivery of drugs encapsulated in liposomes: Natural targeting to macrophages involved in various disease states. J Biol Response Mod 2: 97–100, 1983
Koff WC, Fidler IJ: The potential use of liposome-mediated antiviral therapy. Antiviral Res 228: 495–497, 1985
Fidler IJ, Raz A, Fogler WE, Kirsh R, Bugelski P, Poste G: The design of liposomes to improve delivery of macrophage-augmenting agents to alveolar macrophages. Cancer Res 40: 4460–4466, 1980
Fidler IJ: Therapy of spontaneous metastases by intravenous injection of liposomes containing lymphokines. Science 208: 1469–1471, 1980
Fidler IJ, Sone S, Fogler WE, Smith D, Braun DG, Tarcsay L, Gisler RJ, Schroit AJ: Efficacy of liposomes containing a lipophilic muramyl dipeptide for activating the tumoricidal properties of alveolar macrophages in vivo. J Biol Response Mod 1: 43–55, 1982
Mehta K, Lopez-Berestein G, Hersh EM, Juliano RL: Uptake of liposomes and liposome-encapsulated muramyl dipeptide by human peripheral blood monocytes. J Reticuloendothel Soc 32: 155–164, 1982
Nayar R, Schroit AJ: Generation of pH-sensitive liposomes: Use of larger unilamellar vesicles containing N-succinylphosphatidylethanolamine. Biochemistry 24: 5967–5971, 1985
Poste G, Bucana CD, Raz A, Bugelski P, Kirsh R, Fidler IJ: Analysis of the fate of systemically administered liposomes and implications for their use in drug delivery. Cancer Res 42: 1412–1422, 1982
Schroit AJ, Fidler IJ: Effects of liposome structure and lipid composition on the activation of the tumoricidal properties of macrophages by liposomes containing muramyl dipeptide. Cancer Res 42: 161–167, 1982
Schroit AJ, Galligioni E, Fidler IJ: Factors influencing the in situ activation of macrophages by liposomes containing muramyl dipeptide. Biol Cell 47: 87–94, 1983
Hart IR, Fogler WE, Poste G, Fidler IJ: Toxicity studies of liposome-encapsulated immunomodulators administered intravenously into dogs and mice. Cancer Immunol Immunother 10: 157–166, 1981
Blusse van Oud Alblas A, van der Linden-Schrever B, Mattie H, van Furth R: The effect of glucocorticosteroids on the kinetics of pulmonary macrophages. J Reticuloendothel Soc 30: 1–14, 1981
Key ME, Talmadge JE, Fogler WE, Bucana C, Fidler IJ: 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: 1189–1198, 1982
Xu ZL, 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
Daemen T, Veninga A, Roerdink FH, Scherphof GL: In vitro activation of rat liver macrophages to tumoricidal activity by free or liposome-encapsulated muramyl dipeptide. Cancer Res 46: 4330–4335, 1986
Daemen T, Veninga A, Scherphof GL, Roerdink FH: The activation of Kupffer cells to tumor cytotoxicity with immunomodulators encapsulated in liposomes. In: Kirn A, Knook DL, Wisse E (eds) Cells of the Hepatic Sinusoid. The Kupffer Cell Foundation, Rijswijk, The Netherlands, 1986, pp 379–383
Phillips NC, Rious J, Tsao M: Activation of Kupffer cell tumoricidal activity by liposomes containing lipophilic muramyl dipeptide. Hepatology 8: 1046–1052, 1988
Sone S, Fidler IJ: Synergistic activation by lymphokines and muramyl dipeptide of tumoricidal properties in rat alveolar macrophages. J Immunol 125: 2454–2460, 1980
Sone S, Fidler IJ: In vitro activation of tumoricidal properties in rat alveolar macrophages by synthetic muramyl dipeptide encapsulated in liposomes. Cell Immunol 57: 42–50, 1981
Lopez-Berestein G, Mehta K, Mehta R, Juliano RL, Hersh EM: The activation of human monocytes by liposome-encapsulated muramyl dipeptide analogues. J Immunol 130: 1500–1504, 1983
Sone S, Utsugi T, Tandon P, Ogawara M: A dried preparation of liposomes containing muramyl tripeptide phosphatidylethanolamine as a potent activator of human blood monocytes to the anticancer state. Cancer Immunol Immunother 22: 191–196, 1986
Sone S, Mutsuura S, Ogawara M, Tsubura E: Potentiating effects of muramyl dipeptide and its lipophilic analog encapsulated in liposomes on tumor cell killing by human monocytes. J Immunol 132: 2105–2110, 1984
Kleinerman ES, Erickson KL, Schroit AJ, Fogler WE, Fidler IJ: Activation of tumoricidal properties in human blood monocytes by liposomes containing lipophilic muramyl tripeptide. Cancer Res 43: 2010–2014, 1983
Sone S, Tsubura E: Human alveolar macrophages: Potentiation of their tumoricidal activity by liposome-encapsulated muramyl dipeptide. J Immunol 129: 1313–1317, 1982
Fogler WE, Fidler IJ: The activation of tumoricidal properties in human blood monocytes by muramyl peptides requires a specific intracellular interaction. J Immunol 136: 2311–2316, 1986
Fidler IJ: The In situ induction of tumoricidal activity in alveolar macrophages by liposomes containing muramyl dipeptide is a thymus-independent process. J Immunol 127: 1719–1720, 1981
Fidler IJ, Sone S, Fogler WE, Barnes ZL: Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc Natl Acad Sci USA 78: 1680–1684, 1981
Fidler IJ, Fan D, Ichinose Y: Potent in situ activation of murine lung macrophages and therapy of melanoma metastases by systemic administration of liposomes containing muramyltripeptide phosphatidylethanolamine and interferon gamma. Inv Metastasis 9: 75–88, 1989
Fidler IJ, Schroit AJ: Synergism between lymphokines and muramyl dipeptide encapsulated in liposomes: In situ activation of macrophages and therapy of spontaneous cancer metastasis. J Immunol 133: 515–518, 1984
Eppstein DA, Van der Pas MA, Fraser-Smith EB, Kurahara CG, Felgner PL, Mathews TR, Waters RV, Venuti MC, Jones GH, Metha R, Lopez-Berestein G: Liposome-encapsulated muramyl dipeptide analogue enhances nonspecific host immunity. Int J Immunother 2: 115–126, 1986
Deodhar SD, Barna BP, Edinger M, Chiant T: Inhibition of lung metastases by liposomal immunotherapy in a murine fibrosarcoma model. J Biol Response Mod 1: 27–34, 1982
Lopez-Berestein G, Milas L, Hunter N, Mehta K, Eppstein D, Van der Pas MA, Mathews TR, Hersh EM: Prophylaxis and treatment of experimental lung metastases in mice after treatment with liposome-encapsulated 6-O-steroyl-N-acetyl muramyl-l-amino-butyryl-d-isoglutamine. Clin Exp Metastasis 2: 366–367, 1984
Deodhar SR, James K, Chiang T, Edinger M, Barna B. Inhibition of lung metastases in mice bearing a malignant fibrosarcoma by treatment with liposomes containing human c-reactive protein. Cancer Res 42: 5084–5091, 1982
Phillips NC, Mora ML, Chedid L, Lefrancier P, Bernard JM: Activation of tumoricidal activity and eradication of experimental metastases by freeze-dried liposomes containing a new lipophilic muramyl dipeptide derivative. Cancer Res 45: 128–134, 1985
Philips NC, Tsao M: Inhibition of experimental liver tumor growth in mice by liposomes containing a lipophilic muramyl dipeptide. Cancer Res 49: 936–940, 1989
Brodt P, Blore J, Phillips NC, Munzer JS, Rioux JD: Inhibition of murine hepatic tumor growth by liposomes containing a lipophilic muramyl dipeptide. Cancer Immunol Immunother 28: 54–60, 1989
Thombre P, Deodhar SD: Inhibition of liver metastases in murine colon adenocarcinoma by liposomes containing human c-reactive protein or crude lymphokine. Cancer Immunol Immunother 16: 145–150, 1984
Talmadge JE, Lenz BF, Klabansky R, Simon R, Riggs C, Guo S, Oldham RK, Fidler IJ: Therapy of autochthonous skin cancers in mice with intravenously injected liposomes containing muramyltripeptide. Cancer Res 46: 1160–1163, 1986
Kripke ML: Immunological mechanisms in UV radiation carcinogenesis. Adv Cancer Res 34: 69–106, 1981
Kripke ML: Immunological unresponsiveness induced by ultraviolet radiation. Immunol Rev 80: 87–102, 1984
Fidler IJ: Optimization and limitation of systemic treatment of murine melanoma metastases with liposomes containing muramyl tripeptide phosphatidylethanolamine. Cancer Immunol Immunother 21: 169–173, 1986
Poste G: Liposome targeting in vivo: Problems and opportunities. Biol Cell 47: 19–39, 1983
Sadler TE, Jones DDE, Castro JE: (1979) The effects of altered phagocytic activity on growth of primary and metastatic tumors. In: McBride JF, Stuart A (eds) The Macrophage and Cancer. Econoprint, Edinburgh, 1979, pp 115–163
Fidler IJ, Barnes Z, Fogler WE, Kirsh R, Bugelski P, Poste G: Involvement of macrophages in the eradication of established metastases following intravenous injection of liposome containing macrophage activators. Cancer Res 42: 496–501, 1982
Gillete EL: Spontaneous canine neoplasms as models for therapeutic agents. In: Fidler IJ, White RJ (eds) Design of Models for Testing Cancer Therapeutic Agents. Van Nostrand-Reinhold, New York, 1982, pp 185–192
Brodey RS, Abt DA: Results of surgical treatment in 65 dogs with osteosarcoma. J Am Vet Med Assoc 168: 1032–1038, 1976
MacEwen EG, Kurzman ID, Rosenthal RC, Smith BW, Manley PA, Roush JK, Howard PE: Therapy for osteosarcoma in dogs with intravenous injection of liposomeencapsulated muramyl tripeptide. J Natl Cancer Inst 81: 935–938, 1989
Hisano G, Fidler IJ: Systemic activation of macrophages by liposome-entrapped muramyl tripeptide in mice pretreated with the chemotherapeutic agent Adriamycin. Cancer Immunol Immunother 14: 61–66, 1982
Suit HD: A basis for radiotherapy. In: Flecher GH (ed) Textbook of Radiotherapy. Lea & Febiger, Philadelphia, 1966, pp 65–97
Saiki I, Milas L, Hunter N, Fidler IJ: Treatment of experimental lung metastasis with local thoracic irradiation followed by systemic macrophage activation with liposomes containing muramyl tripeptide. Cancer Res 46: 4966–4960, 1986
Hudson MM, Snyder JS, Jaffe N, Kleinerman ES: In vitro and in vivo effect of Adriamycin therapy on monocyte activation by liposome-encapsulated immunomodulators. Cancer Res 48: 5256–5263, 1988
Kleinerman ES, Hudson MM: Liposome therapy: A novel approach to the treatment of childhood osteosarcoma. In: Lopez-Berestein G, Fidler IJ (eds) Liposomes in the Therapy of Infectious Diseases and Cancer, New Series, Vol. 89. Alan R. Liss, Inc, New York, 1989, pp 71–80
Hanagan JR, Trunet P, LeSher D, Andrejcio K, Frost H: Phase I development of CGP 19835A lipid (MTP-PE encapsulated in liposomes). In: Lopez-Berestein G, Fidler IJ (eds) Liposomes in the Therapy of Infectious Diseases and Cancer. Alan R. Liss, Inc., New York, 1989, pp 305–315
Creaven PJ, Brenner DE, Cowens JW, Huben R, Karakousis C, Han T, Dadey B, Adrejcio K, Cushman MK: Initial clinical trial of muramyl tripeptide derivative (MTP-PE) encapsulated in liposomes: An interim report. In: Lopez-Berestein G, Fidler IJ (eds) Liposomes in the Therapy of Infectious Diseases and Cancer, New Series, Vol. 89. Alan R. Liss, Inc., New York, 1989, pp 297–303
Murray JL, Kleinerman ES, Tatom JR, Cunningham JE, Lepe-Zuniga J, Gutterman JU, Adrejcio K, Fidler IJ, Krakoff IH: A pilot phase I trial of liposomal N-acetylmuramyl-l-alnyl-d-isoglutaminyl-l-alanyl-phosphatidyl- ethanolamine (MTP-PE, CGP 19835A) in cancer patients. In: Lopez-Berestein G, Fidler IJ (eds) Liposomes in the Therapy of Infectious Diseases and Cancer, New Series, Vol. 89. Alan R. Liss, Inc., New York, 1989, pp 329–342
Brownbill AF, Braun DG, Dukor P, Schumann G: Induction of tumoricidal leukocytes by the intranasal application of MTP-PE, a lipophilic muramyl peptide. Cancer Immunol Immunother 20: 11–18, 1985
Fidler IJ, Fogler WE, Brownbill AF, Schumann G: Systemic activation of tumoricidal properties in mouse macrophages and inhibition of melanoma metastases by the oral administration of MTP-PE, a lipophilic muramyl dipeptide. J Immunol 138: 4509–4514, 1987
Schumann G, van Hoogevest P, Fankhauser P, Probst A, Peil A, Court M, Schaffner J-C, Fischer M, Skripsky T, Gracpel P: Comparison of free and liposomal MTP-PE: Pharmacological, toxicological and pharmacokinetic aspects. In: Lopez-Berestein G, Fidler IJ (eds) Liposomes in the Therapy of Infectious Diseases and Cancer, New Series, Vol. 89. Alan R. Liss, Inc, New York, 1989, pp 191–203
Murray JL, Kleinerman ES, Cunningham JE, Tatom JR, Andrejcio K, Lepe-Zuniga J, Lamki LM, Rosenblum MG, Frost H, Gutterman JU, Fidler IJ, Krakoff IH: Phase I trial of liposomal muramyl-tripeptide-phosphatidyl-ethanolamine [MTP-PE (CGP19835A)] in cancer patients. J Clin Oncol 7: 1915–1925, 1989
Zubrod CG, Schneiderman M, Frei E, Brindley C, Gold LG, Shnider B, Oviedo R, Gorman J, Jones RJr, Jonsson U, Colsky J, Chalmers T, Ferguson B, Dederick M, Holland J, Selawry O, Regelson W, Lasagna L, Owens AHJr: Appraisal of methods for the study of chemotherapy of cancer in man: Comparative therapeutic trial of nitrogen mustard and triethylene thiophosphoramide. J Chron Dis 11: 7–33, 1960
Shah RG, Caporale LH, Moore MAS: Characterization of colony-stimulating activity produced by human monocytes and phytohemagglutanin-stimulated lymphocytes. Blood 50: 811–821, 1977
Moore MAS, Warren DJ: Synergy of interleukin-1 and granulocyte colony stimulating factor: In vivo stimulation of stem cell recovery and hematopoietic regeneration following 5-fluorouracil treatment of mice. Proc Natl Acad Sci USA 84: 7134–7138, 1987
Murray JL: Prostaglandin E2 modulation of human monocyte antibody-dependent cell-mediated cytotoxicity against human red blood cells. Cell Immunol 71: 196–201, 1982
Kleinerman ES, Kurzrock R, Wyatt D, Quesada JR, Gutterman JU, Fidler IJ: Activation or suppression of the tumoricidal properties of monocytes from cancer patients following treatment with human recombinant γ-inteferon. Cancer Res 46: 5401–5405, 1986
Kleinerman ES, Murray JL, Snyder JS, Cunningham JE, Fidler IJ: Activation of tumoricidal properties in monocytes from cancer patients following intravenous administration of liposomes containing muramyl tripeptide phosphatidylethanolamine. Cancer Res 49: 4665–4670, 1989
Bases RE, Krakoff IH: Studies of serum cholesterol levels in leukemia. J Reticuloendothelial Endothel Soc 2: 8–14, 1965
Nimer SD, Champlin RE, Golde DW: Serum cholesterol-lowering activity of granulocyte-macrophage colony-stimulating factor. J Amer Med Assoc 260: 3297–3300, 1988
Cai HJ, He ZG, Ding YN: Effects of monocyte macrophage stimulation on hepatis lipoprotein receptors. Biochem Biophys Acta 959: 334–342, 1988
Goldstein JL, Ho YK, Basu SK, Brown D: Binding site of macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci USA 76: 333–337, 1979
Fey GH, Fuller GM: Regulation of acute phase gene expression by inflammatory mediators. Mol Biol Med 4: 323–338, 1987
Richardson VJ, Ryman BE, Jewkes RF, Jeyasingh K, Tattersall MNH, Newlands ES, Kaye SB: Tissue distribution and tumor localization of 99mTechnetium-labeled liposomes in cancer patients. Br J Cancer 40: 35–43, 1979
Lopez-Berestein G, Kasi L, Rosenblum MG, Haynie T, Jahns M, Glenn H, Mehta R, Mavligit GM, Hersh EM: Clinical pharmacology of 99mTc-labeled liposomes in patients with Hodgkins disease. J Nucl Med 26: 743–749, 1985
Perez-Soler R, Lopez-Berestein G, Kasi LP, Cabanillas F, Jahns M, Glenn H, Hersh EM, Haynic T: Distribution of technetium-99m-labeled multilamellar liposomes in patients with Hodgkins disease. J Nucl Med 26: 743–749, 1985
Richardson VJ, Jeyaingh K, Jewkes RF, Ryman BE, Tattersall MHN: Possible tumor localization of Tc-99m-labeled liposomes: Effect of lipid composition, charge, and liposome size. J Nucl Med 19: 1049–1054, 1978
Fidler IJ, Poste G: Macrophage-mediated destruction of malignant tumor cells and new strategies for the therapy of metastatic disease. Springer Semin Immunopathol 5: 161–174, 1982
Silverberg E, Lubera J: Cancer statistics. Cancer 3: 5–22, 1988
Himel HN, Liberati A, Gelber RD, Chalmers TC: Adjuvant chemotherapy for breast cancer: A pooled estimate based on published randomized control trials. JAMA 256: 1148, 1986
de Lorimier AA, Harrison NR: Tumors in childhood: In: Way LW (ed) Current Surgical Diagnosis and Treatment. Appleton and Lang, San Mateo, CA, 1988, pp 1128–1130
Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA, Simpson C, Carter C, Bock S, Schwartzenbruber D, Wei JP, White DE: Use of tumor infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. N Engl J Med 319: 1676–1680, 1988
Laurie JA, Moertel CG, Fleming TR, Wieand HS, Leigh JE, Rubin J, McCormack GW, Gerstner JB, Krook JE, Malliard J, Twito DI, Morton RF, Tschetter LK, Barlow JF: Surgical adjuvant therapy of large-bowel carcinoma: An evaluation of levamisole and the combination of levamisole and fluorouracil. J Clin Oncol 7: 1447–1456, 1989
Wadler S, Lyver A, Goldman M, Wiernik PH: Therapy with 5-fluorouracil and recombinant alpha-2 interferon in refractory GI malignancies. Proc Am Soc Clin Oncol (Abstract) 8: 99, 1989
Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316: 889–897, 1987
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Whitworth, P.W., Pak, C.C., Esgro, J. et al. Macrophages and cancer. Cancer Metast Rev 8, 319–351 (1990). https://doi.org/10.1007/BF00052607
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DOI: https://doi.org/10.1007/BF00052607