Toxicity studies of liposome-encapsulated immunomodulators administered intravenously to dogs and mice

Hart, Ian R.; Fogler, William E.; Poste, George; Fidler, Isaiah J.

doi:10.1007/bf00205887

Cited by 24 publications

(8 citation statements)

References 28 publications

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“…(23). Second, extensive toxicity studies in mice and-dogs demonstrated that, at the dose used here, these MLV are not, toxic (22).…”

Section: Discussionmentioning

confidence: 75%

“…Encapsulation of MDP or CME medium within liposomes was achieved by using methods similar to those described (20,21). We used PtdSer/PtdCho MLV as carriers for MDP because they are not toxic at the dose used here (22) and are arrested efficiently in the lungs (in addition to organs of the reticuloendothelial system) after intravenous administration (23). MLV Macrophage-Mediated Cytotoxicity Assay.…”

mentioning

confidence: 99%

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Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide.

Fidler¹,

Sone²,

Fogler³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

289

130

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The multiple systemic administration of multilamellar liposomes composed of phosphatidylserine and phosphatidylcholine (molar ratio 3:7) that contained water-soluble muramyl dipeptide (MDP) activated alveolar macrophages to become tumoricidal and eradicated established spontaneous pulmonary and lymph node metastases. Spontaneously metastasizing melanoma cells were injected into the footpads of mice. After 4-5 weeks, the tumors were resected by a midfemoral amputation; 3 days later, twice-weekly injections of liposomes were initiated and continued for 4 weeks. In some experiments the mice were killed 2 weeks after the final treatment. Seventy-four Percent of animals injected with liposomes containing MDP were free of visible metastases. In a separate life-span experiment, 60% of mice treated with liposome-encapsulated MDP were tumor-free 120 days after the last liposome treatment or 110 days after all control mice treated with free MDP or control liposome preparations had died of disseminated cancer. These data suggest that the systemic administration of liposomes containing MDP, or similar compounds that produce macrophage activation, may provide an additional useful approach to the therapeutic regimens currently used to eradicate cancer metastases.Metastasis of malignant neoplasms is responsible for most therapeutic failures in clinical oncology (1-3). Recent studies suggested that metastases can result from the proliferation of a minor subpopulation of cells within the primary tumor and that tumors can be heterogeneous with regard to many phenotypic characteristics such as drug sensititivity and metastatic potential (1-3). Such biological diversity among metastases implies that successful therapy of disseminated disease must include a regimen that acts by a mechanism independent of this heterogeneity.One biological agent that appears to function against tumor cells without regard to their phenotypic diversity is the activated macrophage. At least in vitro, macrophages can distinguish tumorigenic from nontumorigenic cells by a mechanism that is independent of such phenotypic characteristics as drug sensitivity, metastatic potential, and antigenicity (4). Moreover, to date, attempts to select in vitro tumor cells resistant to macrophage-mediated cytotoxicity have been unsuccessful (5).The increasing evidence that macrophages are important in host defense against neoplasia has stimulated interest in agents that can enhance macrophage-mediated destruction of tumor cells. Normal macrophages can be activated to become tumoricidal by various agents such as lymphokines and by whole microorganisms or their products such as endotoxins (6). However, the use of whole viable microorganisms or their products to activate macrophages in vivo has been hampered by a number of undesirable side effects (7).The search for synthetic compounds that are relatively nontoxic yet possess immune potentiating activities has resulted in the demonstration that N-acetylmuramyl-L-alanyl-D-isoglutamine [muramyl dipeptide. (MDP), Mr 49...

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“…(23). Second, extensive toxicity studies in mice and-dogs demonstrated that, at the dose used here, these MLV are not, toxic (22).…”

Section: Discussionmentioning

confidence: 75%

mentioning

confidence: 99%

Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide.

Fidler¹,

Sone²,

Fogler³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

289

130

View full text Add to dashboard Cite

show abstract

“…First, studies of the body distribution of liposomes of differing size and phospholipid composition demonstrated that optimal localization and retention of liposomes in the lungs were achieved with these negatively charged liposomes at a 1:1 mole ratio (13). Second, at the dose used here, MAF-containing liposomes of this composition are not toxic and activate alveolar macrophages in mice and rats to become tumoricidal after being injected intravenously (14). In conclusion, the systemic administration of liposomes containing a macrophage activator can eradicate established pulmonary metastases originating from a subcutaneous melanoma.…”

mentioning

confidence: 71%

Therapy of Spontaneous Metastases by Intravenous Injection of Liposomes Containing Lymphokines

Fidler

1980

Science

186

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Mice of two different strains were injected subcutaneously with spontaneously metastasizing syngeneic melanomas. After 4 to 6 weeks, the local tumors were removed and, 3 days after surgery, treatment of the metastases was initiated. The treatment consisted of intravenous injections of liposomes containing lymphokines or control supernatant fluids. Liposomes were injected twice weekly for 3 weeks, and the mice were killed 2 weeks later. Seventy-three percent of the mice injected with liposomes containing lymphokines were free of metastases, whereas only 10 percent of the mice treated with control liposomes were tumor-free. These experiments suggest that this form of therapy may provide a valuable addition to the more conventional approaches to the eradication of cancer metastases.

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“…During the last several years, attention has focused on the use of synthetic phospholipid vesicles (liposomes) to deliver drugs to various organ sites in vivo [129][130][131][132][133][134][135][136]. Such intracellular delivery avoids the problems of dilution, protein binding, and rapid clearance and minimizes the elicitation of undesirable side effects [144][145][146][147]. We have taken advantage of this natural fate of liposomes to deliver biological agents to cells of the reticuloendothelial system (RES), resulting in the activation of these phagocytic cells to the tumoricidal state [136][137][138][139][140][141][142][143][144].…”

Section: Systemic Activation Of Macrophages By Liposomes Containing Imentioning

confidence: 99%

Macrophages and cancer

et al. 1990

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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 nonneoplastic 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 start 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 10(6) 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.(ABSTRACT TRUNCATED AT 400 WORDS)

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Toxicity studies of liposome-encapsulated immunomodulators administered intravenously to dogs and mice

Cited by 24 publications

References 28 publications

Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide.

Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide.

Therapy of Spontaneous Metastases by Intravenous Injection of Liposomes Containing Lymphokines

Macrophages and cancer

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