Skip to main content

Advertisement

SpringerLink
Log in

Therapy of disseminated melanoma by liposome-activated macrophages

  • World Progress In Surgery
  • Published:
World Journal of Surgery Aims and scope Submit manuscript

Abstract

The uncontrolled growth of metastases is a major cause of death from melanoma. Metastases arise from the nonrandom spread of specialized malignant cells that preexist within a primary neoplasm. Macrophages are activated to become tumoricidal by interaction with phospholipid vesicles (liposomes) containing immunomodulators recognize and destroy neoplastic cellsin vitro andin vivo while leaving nonneoplastic cells unharmed. The mechanism(s) by which macrophages discriminate between tumorigenic and normal cells 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.

Intravenously administered liposomes are cleared from the circulation by phagocytic cells. The administration of such liposomes has been shown to activate macrophagesin situ and to bring about eradication of cancer metastases in several experimental tumor systems and in dogs with spontaneous osteogenic sarcoma. Macrophage destruction of metastasesin vivo is significant, provided that the 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 systemic activation of macrophages. Macrophage-directed therapy has been studied in several human protocols, yielding important biological information about the safe use of liposome-encapsulated macrophage activators in cancer patients.

Résumé

La croissance incontrolable des métastases est une des principales causes de décès par mólanome. Les métastases surveillment du fait de la dissémination non aléatoire de cellules malignes différenciées qui préxistent au sein de la tumeur primitive. Des macrophages, activés pour être tumoricides par interaction avec des vésicules phospholipidiques (liposomes) contenant des immunomodulateurs, reconnaissent et détruisent des cellules néoplasiquesin vitro etin vivo mais respectent les cellules non tumorales. Le(s) mécanisme(s) par le(s)quel(s) les macrophages différencient cellules tumorales et cellules normales est (sont) indépendant(s) des caractéristiques des cellules tumorales comme l'immunogénicité, les capacités à métastaser et la sensibilité aux drogues cytotoxiques. Bien plus, la destruction des cellules tumorales par les macrophages ne semble pas liée au développement d'une résistance des cellules tumorales.

Après injection intraveineuse, les liposomes sont éliminés de la circulation par des cellules phagocytaires. Il a été demontré que l'administration de tels liposomes active les macrophagesin situ et contribue à l'éradication des métastases cancéreuses dans plusieurs systèmes tumoraux expérimentaux et chez le chien atteint de sarcome ostéogénique spontané. La destruction des métastases par les macrophagesin vivo est importante à condition que la masse tumorale au début du traitement soit minimale. Pour cette raison, nous avons expérimenté différentes méthodes pour obtenir une réduction maximale des métastases. Les moyens utilisés avant l'activation systémique des macrophages ont été la chimiothérapie et la radiothérapie. Le traitement par les macrophages a été étudié par plusieurs protocoles chez l'homme, fournissant une information biologique importante sur l'innocuité de l'utilisation des activateurs de macrophages sous forme de liposomes encapsulés chez les patients cancéreux.

Resumen

El crecimiento incontrolado de metástasis es una causa mayor de muerte en pacientes con melanoma. Las metástasis se originan en la extensión al azar de células malignas especializadas que preexisten en el tumor primario. Los macrófagos activados para hacer tumoricidas por la interacción de vesículas de fosfolípidos (liposomas) que contienen inmunomoduladores reconocen y destruyen las células neoplásicasin vitro ein vivo, en tanto que no lesionan las células no neoplásicas. El mecanismo(s) por medio del cual los macrófagos discriminan las células tumorigénicas de las células normales es independiente de características celulares tales como inmunogenecidad, potencial metástasico y sensibilidad a drogas citotóxicas. Además, la destrucción macrofágica de las células tumorales aparentemente no está asociada con el desarrollo de resistencia por parte de las células tumorales.

Liposomas administrados por vía intravenosa son depurados de la circulación por las células fagocítica. Se ha demostrado que la administración de tales liposomas activa los macrófagosin situ y que logra la erradicación de metástasis en varios sistemas y tumorales experimentales y en perros con sarcoma osteogénico espontáneo. La destrucción macrofágica de las metástasisin vivo es significativa, siempre y cuando la carga tumoral sea mínima en el momento del tratamiento. Es por esta razón que hemos estado investigando varios métodos para lograr máxima citorreducción en las metástasis mediante modalidades tales como quimioterapia o radioterapia antes de la activación sistémica de los macrófagos. La terapia macrófagodirigida ha sido estudiada en varios protocolos humanos, y ha provisto importante información biológica sobre la seguridad del uso de activadores liposoma-encapsulados de macrófagos en pacientes con cáncer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Fidler, I.J.: Critical factors in the biology of human cancer metastasis: Twenty-eighth G.H.A. Clowes Memorial Award Lecture. Cancer Res.50:6130, 1990

    PubMed  Google Scholar 

  2. Fidler, I.J., Poste, G.: The cellular heterogeneity of malignant neoplasms: Implications for adjuvant chemotherapy. Semin. Oncol.12:207, 1985

    PubMed  Google Scholar 

  3. Poste, G., Fidler, I.J.: The pathogenesis of cancer metastasis. Nature283:139, 1979

    Google Scholar 

  4. Fidler, I.J., Kripke, M.L.: Metastasis results from preexisting variant cells within a malignant tumor. Science197:893, 1977

    PubMed  Google Scholar 

  5. Talmadge, J.E., Wolman, S.R., Fidler, I.J.: Evidence for the clonal origin of spontaneous metastases. Science217:361, 1982

    PubMed  Google Scholar 

  6. Fidler, I.J.: Macrophages and metastasis—a biological approach to cancer therapy: Presidential address. Cancer Res.45:4714, 1985

    PubMed  Google Scholar 

  7. Fidler, I.J., Schroit, A.J.: Recognition and destruction of neoplastic cells by activated macrophages: Discrimination of altered self. Biochim. Biophys. Acta948:151, 1988

    PubMed  Google Scholar 

  8. Hibbs, J. B., Jr.: Discrimination between neoplastic and nonneoplastic cellsin vitro activated macrophages. J. Natl. Cancer Inst.53:1487, 1974

    PubMed  Google Scholar 

  9. Norbury, K.C., Kripke, M.I.: Ultraviolet-induced carcinogenesis in mice treated with silica, trypan blue or pyran copolymer. J. Reticuloendothel. Soc.26:827, 1979

    PubMed  Google Scholar 

  10. Sadler, T.E., Jones, D.D.E., Castro, J.E.: The effects of altered phagocytic activity on growth of primary and metastatic tumors. In The Macrophage and Cancer, J.F. McBride, A. Stuart, editors, Edinburgh, Econoprint, 1979, pp. 115–163

    Google Scholar 

  11. 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. Cancer25:617, 1980

    PubMed  Google Scholar 

  12. Fidler, I.J.: Inhibition of pulmonary metastasis by intravenous injection of specifically activated macrophages. Cancer Res.34:1074, 1974

    PubMed  Google Scholar 

  13. Liotta, L.A., Gattozzi, C., Kleinerman, J.: Reduction of tumor cell entry into vessels by BCG-activated macrophages. Br. J. Cancer36:639, 1977

    PubMed  Google Scholar 

  14. Normann, S.J.: Macrophage infiltration and tumor progression. Cancer Metastasis Rev.4:277, 1985

    PubMed  Google Scholar 

  15. Bugelski, P.J., Kirsh, R.L., Sowinski, J.M., Poste, G.: Changes in the macrophage content of lung metastases at different stages in tumor growth. Am. J. Pathol.118:419, 1985

    PubMed  Google Scholar 

  16. Schackert, G., Simmons, R.D., Buzbee, T.M., Hume, D.A., Fidler, I.J.: Macrophage infiltration into experimental brain metastasis occurs through an intact blood-brain barrier. J. Natl. Cancer Inst.80:1027, 1988

    PubMed  Google Scholar 

  17. Fidler, I.J., Raz, A.: The induction of tumoricidal capacities in mouse and rat macrophages by lymphokines. In Lymphokines, E. Pick, editor, New York, Academic Press, 1981, pp. 345–363

    Google Scholar 

  18. Allison, A.C.: Mode of action of immunological adjuvants. J. Reticuloendothel. Soc.26:619, 1979

    PubMed  Google Scholar 

  19. Lederer, E.: Synthetic immunostimulants derived from the bacterial cell wall. J. Med. Chem.23:819, 1980

    PubMed  Google Scholar 

  20. Fogler, W.E., Fidler, I.J.: Modulation of the immune response by muramyl dipeptide. In Immune Modulation Agents and Their Mechanisms, M.A. Chirigos, R.L. Fenichel, editors, New York, Marcel Dekker, 1984, pp. 499–512

    Google Scholar 

  21. Saiki, I., Sone, S., Fogler, W.E., Kleinerman, E.S., Lopez-Berestein, G., Fidler, I.J.: 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, 1985

    PubMed  Google Scholar 

  22. Hibbs, J.B. Jr.: Discrimination between neoplastic and nonneoplastic cells byin vitro activated macrophages. J. Natl. Cancer Inst.53:1487, 1974

    PubMed  Google Scholar 

  23. Bucana, C.D., Hoyer, L.C., Schroit, A.J., Kleinerman, E.S., Fidler, I.J.: Ultrastructural studies of the interaction between liposome-activated human blood monocytes and allogeneic tumor cellsin vitro. Am. J. Pathol.112:101, 1983

    PubMed  Google Scholar 

  24. Fogler, W.E., Fidler, I.J.: Nonselective destruction of murine neoplastic cells by syngeneic tumoricidal macrophages. Cancer Res.45:14, 1985

    PubMed  Google Scholar 

  25. Fidler, I.J., Kleinerman, E.S.: Lymphokine-activated human blood monocytes destroy tumor cells but not normal cells under cocultivation conditions. J. Clin. Oncol.2:937, 1984

    PubMed  Google Scholar 

  26. Poste, G., Kirsh, R., Fidler, I.J.: Rapid decay of tumoricidal activity and loss of responsiveness to lymphokines in inflammatory macrophages. Cancer Res.39:2582, 1979

    PubMed  Google Scholar 

  27. Kleinerman, E.S., Schroit, A.J., Fogler, W.E., Fidler, I.J.: Tumoricidal activity of human monocytes activatedin vitro by free and liposome-encapsulated human lymphokines. J. Clin. Invest.72:1, 1983

    PubMed  Google Scholar 

  28. Fidler, I.J.: Targeting of immunomodulators to mononuclear phagocytes for therapy of cancer. Advances in Drug Delivery Reviews2:69, 1988

    Google Scholar 

  29. Daoud, S.S., Hume, L.R., Juliano, R.L.: Liposomes in cancer therapy. Advances in Drug Delivery Reviews3:405, 1989

    Google Scholar 

  30. Schroit, A.J., Fidler, I.J.: 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, 1982

    PubMed  Google Scholar 

  31. Fidler, I.J.: Thein situ induction of tumoricidal activity in alveolar macrophages by liposomes containing muramyl dipeptide is a thymus-independent process. J. Immunol.127:1719, 1981

    PubMed  Google Scholar 

  32. Fidler, I.J.: Therapy of spontaneous metastases by intravenous injection of liposomes containing lymphokines. Science208: 1469, 1980

    PubMed  Google Scholar 

  33. Fidler, I.J., Sone, S., Fogler, W.E., Smith, D., Braun, D.G., Tarcsay, L., Gisler, R.J., Schroit, A.J.: Efficacy of liposomes containing a lipohilic muramyl dipeptide for activating the tumoricidal properties of alveolar macrophagesin vivo. J. Biol. Response Mod.1:43, 1982

    Google Scholar 

  34. Eppstein, D.A., Van der Pas, M.A., Fraser-Smith, E.B., Kurahara, C.G., Felgner, P.L., Mathews, T.R., Waters, R.V., Venuti, M.C., Jones, G.H., Metha, R., Lopez-Berestein, G.: Liposome-encapsulated muramyl dipeptide analogue enhances non-specific host immunity. Int. J. Immunother.2:115, 1986

    Google Scholar 

  35. Lopez-Berestein, G., Milas L., Hunter, N., Mehta, K., Eppstein, D., Van der Pas, M.A., Mathews, T.R., Hersh, E.M.: 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. Metastasis2:366, 1984

    Google Scholar 

  36. Phillips, N.C., Mora, M.L., Chedid, L., Lefrancier, P., Bernard, J.M.: Activation of tumoricidal activity and eradication of experimental metastases by freeze-dried liposomes containing a new lipophilic muramyl dipeptide derivative. Cancer Res.45:128, 1985

    PubMed  Google Scholar 

  37. Deodhar, S.R., 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, 1982

    PubMed  Google Scholar 

  38. Phillips, N.C., Tsao, M.: Inhibition of experimental liver tumor growth in mice by liposomes containing a lipophilic muramyl dipeptide. Cancer Res.49:936, 1989

    PubMed  Google Scholar 

  39. Brodt, P., Blore, J., Phillips, N.C., Munzer, J.S., Rioux, J.D.: Inhibition of murine hepatic tumor growth by liposomes containing a lipophilic muramyl dipeptide. Cancer Immunol. Immunother.28:54, 1989

    PubMed  Google Scholar 

  40. Talmadge, J.E., Lenz, B.F., Klabansky, R., Simon, R., Riggs, C., Guo, S., Oldham, R.K., Fidler, I.J.: Therapy of autochthonous skin cancers in mice with intravenously injected liposomes containing muramyltripeptide. Cancer Res.46:1160, 1986

    PubMed  Google Scholar 

  41. Fidler, I.J.: Optimization and limitation of systemic treatment of murine melanoma metastases with liposomes containing muramyl tripeptide phosphatidylethanolamine. Cancer Immunol. Immunother.21:169, 1986

    PubMed  Google Scholar 

  42. Fidler, I.J., Fan, D., Ichinose, Y.: Potentin situ activation of murine lung macrophages and therapy of melanoma metastases by systemic administration of liposomes containing muramyltripeptide phosphatidylethanolamine and interferon gamma. Inv. Metastasis9:75, 1989

    Google Scholar 

  43. Fidler, I.J., Barnes, Z., Fogler, W.E., 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, 1982

    PubMed  Google Scholar 

  44. Gillete, E.L.: Spontaneous canine neoplasms as models for therapeutic agents. In Design of Models for Testing Cancer Therapeutic Agents, I.J. Fidler, R.J. White, editors, New York, Van Nostrand-Reinhold, 1982, pp. 185–192

    Google Scholar 

  45. MacEwen, E.G., Kurzman, I.D., Rosenthal, R.C., Smith, B.W., Manley, P.A., Roush, J.K., Howard, P.E.: Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. J. Natl. Cancer Inst.81:935, 1989

    PubMed  Google Scholar 

  46. Creaven, P.J., Cowens, J.W., Brenner, D.E., Dadey, B.M., Han, T., Huben, R., Karakousis, C., Frost, H., LeSher, D., Hanagan, J., Andrejcio, K., Cushman, M.K.: Initial clinical trial of the macrophage activator muramyl tripeptide-phosphatidylethanolamine encapsulated in liposomes in patients with advanced cancer. J. Biol. Response Mod. 9:492, 1990

    PubMed  Google Scholar 

  47. Urba, W.J., Hatmann, L.C., Longo, D.L., Steis, R.G., Smith II J.W., Kedar, I., Creekmore, S., Sznol, M., Conlon, K., Kopp, W.C., Huber, C., Herold, M., Alvord, W.G., Snow, S., Clark, J.W.: Phase I and immunomodulatory study of a muramyl peptide, muramyl tripeptide phosphatidylethanolamine. Cancer Res.50:2979, 1990

    PubMed  Google Scholar 

  48. Murray, J.L., Kleinerman, E.S., Cunningham, J.E., Tatom, J.R., Andrejcio, K., Lepe-Zuniga, J., Lamki, L.M., Rosenblum, M.G., Frost, H., Gutterman, J.U., Fidler, I.J., Krakoff, I.H.: Phase I trial of liposomal muramyl-tripeptide-phosphatidylethanolamine [MTP-PE PE (CGP 19835A)] in cancer patients. J. Clin. Oncol.7:1915, 1989

    PubMed  Google Scholar 

  49. Brownbill, A.F., Braun, D.G., Dukor, P., Schumann, G.: Induction of tumoricidal leukocytes by the intranasal application of MTP-PE, a lipophilic muramyl peptide. Cancer Immunol. Immunother.20:11, 1985

    PubMed  Google Scholar 

  50. Fidler, I.J., Fogler, W.E., Brownbill, A.F., 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, 1987

    PubMed  Google Scholar 

  51. Poste, G.: Liposome targetingin vivo: Problems and opportunities. Biol. Cell47:19, 1983

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell Biology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, HMB 173, 77030, Houston, Texas, USA

    Isaiah J. Fidler D.V.M., Ph.D.

Authors
  1. Isaiah J. Fidler D.V.M., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fidler, I.J. Therapy of disseminated melanoma by liposome-activated macrophages. World J. Surg. 16, 270–276 (1992). https://doi.org/10.1007/BF02071531

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02071531

Keywords

Search

Navigation