Skip to main content
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1992 Jul;34(4):211–220. doi: 10.1007/BF01741788

Unique histological changes in lung metastases of osteosarcoma patients following therapy with liposomal muramyl tripeptide (CGP 19835A lipid)

Eugenie S Kleinerman 1,2,, Austin K Raymond 3, Corazon D Bucana 1, Norman Jaffe 2, Michael B Harris 4, Irwin H Krakoff 5, Robert Benjamin 6, Isaiah J Fidler 1
PMCID: PMC11038889  PMID: 1537053

Abstract

We have recently begun a phase II trial in patients with osteosarcoma who developed pulmonary metastases during adjuvant chemotherapy or who presented with pulmonary metastases that persisted despite chemotherapy. Eligible patients were rendered free of visible disease by surgery. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (MTP-PE, CGP 19835A lipid) (2 mg/m2) was infused twice weekly for 3 months. In five patients, a single tumor nodule recurred within 6 weeks after completion of therapy. These lesions were resected and submitted for pathological examination. Tissue specimens obtained after therapy were compared to those obtained before therapy. All the patients showed a histological change in the characteristics of the pulmonary tumors. In three patients, peripheral fibrosis surrounded the tumor and inflammatory cell infiltration and neovascularization were present. This is in contrast to central necrosis, with viable peripheral tumor cells and no inflammatory response observed in lesions resected following chemotherapy. In a fourth case, evidence of early fibrotic changes was found. This and the fifth case showed a change in malignant characteristics, from high grade before liposomal therapy to low grade after therapy. The present study provides evidence for a biological effect of liposomal MTP-PE.

Key words: Liposomal therapy, Fibrosis

References

  • 1.Dannenberg AM, Jr, Thomashefski JF., Jr . Pathogenesis of pulmonary tuberculosis. In: Fishman AP, editor. Pulmonary diseases and disorders, 2nd edn, vol 3. New York: McGraw-Hill; 1988. p. 1821. [Google Scholar]
  • 2.Delabie J, Dewolf-Peters C, Van Den Oord JJ, Desmet J. Differential expression of the calcium-binding proteins MRP8 and MRP14 in granulomatous conditions: an immunohistochemical study. Clin Exp Immunol. 1990;81:123. doi: 10.1111/j.1365-2249.1990.tb05301.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Deodhar S. Regulation of expression of the cell adhesion receptors, integrins, by recombinant human interleukin-1β in human osteosarcoma cells: Inhibition of cell proliferation and stimulation of alkaline phosphatase activity. J Cell Physiol. 1989;138:291. doi: 10.1002/jcp.1041380210. [DOI] [PubMed] [Google Scholar]
  • 4.Eilber F, Giuliano A, Eckardt J, Patterson K, Moseley S, Goodnight J. Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol. 1987;5:21. doi: 10.1200/JCO.1987.5.1.21. [DOI] [PubMed] [Google Scholar]
  • 5.Fidler IJ. Macrophages and metastasis: a biological approach to cancer therapy. Cancer Res. 1985;45:4714. [PubMed] [Google Scholar]
  • 6.Fidler IJ. Immunomodulation of macrophages for cancer and antiviral therapy. In: Tomlinson E, Davis SS, editors. Site-specific drug delivery. New York: Wiley; 1986. p. 111. [Google Scholar]
  • 7.Fidler IJ, Barnes Z, Fogler WE, Kirsh R, Gubelski P, Poste G. Involvement of macrophages in the eradication of established metastases following intravenous injection of liposomes containing macrophage activators. Cancer Res. 1982;42:496. [PubMed] [Google Scholar]
  • 8.Fidler IJ, Sone S, Fogler WE, Barnes Z (1982) Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Yearbook of cancer. [DOI] [PMC free article] [PubMed]
  • 9.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. 1984;73:447. doi: 10.1093/jnci/73.2.447. [DOI] [PubMed] [Google Scholar]
  • 10.Goorin AM, Perez-Atayde A, Gebhardt M, Anderson JW, Wilkinson RH, Delorey MJ, Watts H, Link M, Jaffe N, Frei E, III, Abelson HT. Weekly high-dose methotrexate and doxorubicin for osteosarcoma: The Dana-Farber Cancer Institute/The Children's Hospital Study III. J Clin Oncol. 1987;5:1178. doi: 10.1200/JCO.1987.5.8.1178. [DOI] [PubMed] [Google Scholar]
  • 11.Key ME, Talmadge JE, Fogler WE, Bucana CD, 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. 1982;69:1189. [PubMed] [Google Scholar]
  • 12.Kindler V, Sappino A-P, Grau GE, Piguet P-F, Vassalli P. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989;56:731. doi: 10.1016/0092-8674(89)90676-4. [DOI] [PubMed] [Google Scholar]
  • 13.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. 1983;43:2010. [PubMed] [Google Scholar]
  • 14.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. 1989;49:4665. [PubMed] [Google Scholar]
  • 15.Kleinerman ES, Snyder JS, Jaffe N. Influence of chemotherapy administration on monocyte activation by liposomal MTP-PE in children with osteosarcoma. J Clin Oncol. 1991;9:259. doi: 10.1200/JCO.1991.9.2.259. [DOI] [PubMed] [Google Scholar]
  • 16.Lachman LB, Dinarello CA, Llansa ND, Fidler IJ. Natural and recombinant human interleukin 1-β is cytotoxic for human melanoma cells. J Immunol. 1986;136:3098. [PubMed] [Google Scholar]
  • 17.Link MP, Goorin AM, Miser AW, Green AA, Pratt CG, Belasco JB, Pritchard J, Malpas JS, Baker AR, Kirkpatrick JA, Ayala AG, Shuster JJ, Abelson UT, Simone JV, Vietti TJ. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med. 1986;314:1600. doi: 10.1056/NEJM198606193142502. [DOI] [PubMed] [Google Scholar]
  • 18.Lovett D, Kozan B, Hadam M, Resch K, Gemsa D. Macrophage cytotoxicity: interleukin 1 as a mediator of tumor cytostasis. J Immunol. 1986;136:340. [PubMed] [Google Scholar]
  • 19.MacEwen EG, Kurzman ID, Rosenthal RC, Smith BW, Manley PA, Roush JK, Howar PE. Therapy for osteosarcoma in dogs with intravenous injection of liposome-encapsulated muramyl tripeptide. J Natl Cancer Inst. 1989;81:935. doi: 10.1093/jnci/81.12.935. [DOI] [PubMed] [Google Scholar]
  • 20.Murray JL, Kleinerman ES, Cunningham JE, Tatom JR, Andrejcio K, Lepe-Zuniga J, Lumki LM, Rosenblum MG, Frost H, Gutterman JU, Fidler IJ, Krakoff I. Phase I trial of liposomal muramyl tripeptide phosphatidyl-ethanolamine in cancer patients. J Clin Oncol. 1989;7:1915. doi: 10.1200/JCO.1989.7.12.1915. [DOI] [PubMed] [Google Scholar]
  • 21.Odink K, Cerletti N, Bruggen J, Clerc RG, Tarcsay L, Zwadlo G, Gerhard SG, Schlegel R, Sorg C. Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis. Nature. 1987;330:80. doi: 10.1038/330080a0. [DOI] [PubMed] [Google Scholar]
  • 22.Old LJ. Tumor necrosis factor (TNF) Science. 1985;230:630. doi: 10.1126/science.2413547. [DOI] [PubMed] [Google Scholar]
  • 23.Onozaki K, Matsushima K, Aggarwal BB, Oppenheim JJ. Human interleukin 1 is a cytocidal factor for several tumor cell lines. J Immunol. 1985;135:3962. [PubMed] [Google Scholar]
  • 24.Poste G, Bucana C, 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. 1982;42:1412. [PubMed] [Google Scholar]
  • 25.Putnam JB, Jr, Roth JA, Wesley MN, Johnston MR, Rosenberg SA. Analysis of prognostic factors in patients undergoing resection of pulmonary metastases from soft tissue sarcomas. J Thorac Cardiovasc Surg. 1984;87:260. [PubMed] [Google Scholar]
  • 26.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. 1982;43:161. [PubMed] [Google Scholar]
  • 27.Sone S, Utsugi T, Tandon P, Ogawara M. A dried preparation of liposomes containing muramyl tripeptide phosphatidylehtanolamine as a potent activator of human blood monocytes to the antitumor state. Cancer Immunol Immunother. 1986;22:191. doi: 10.1007/BF00200032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Sugarman BJ, Aggarwal BB, Hass PE, Figari MA, Palladino MA, Jr, Shepard HM. Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science. 1985;230:943. doi: 10.1126/science.3933111. [DOI] [PubMed] [Google Scholar]
  • 29.Urban JL, Shepard HM, Rothstein JL, Sugarman BJ, Schreiber H. Tumor necrosis factor: a potent effector molecule for tumor cell killing by activated macrophages. Proc Natl Acad Sci USA. 1986;83:5233. doi: 10.1073/pnas.83.14.5233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Van Hoogevest P, Fankhauser P. An industrial liposomal dosage form for muramyl-tripeptide-phosphatidylethanolamine (MTP-PE) In: Lopez-Berestein G, Fidler IJ, editors. Liposomes in the therapy of infectious diseases and cancer. New York: Liss; 1989. p. 453. [Google Scholar]
  • 31.Wold LE, Unni KK, Beabout JW, Sim FH, Dahlin DC. Dedifferentiated parosteal osteosarcoma. J Bone Joint Surg. 1984;66(A):53. [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES