Skip to main content

Advertisement

SpringerLink
Log in

Liposomal encapsulated anthracyclines: new therapeutic horizons

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

After two decades of work in liposomal formulations for clinical use, two preparations containing doxorubicin (Doxil, ALZA, Pablo Alto, CA; and Evacet [TLC D-99], The Liposome Company, Princeton, NJ), and one containing daunorubicin (DaunoXome; Gilead Sciences, Foster City, CA) have been undergoing widespread clinical study. Results have lived up to the promise that liposomal encapsulation may lead to toxicity attenuation, while retaining or even enhancing the efficacy of the parent anthracyclines. The eventual role of these agents in clinical practice is being defined in a number of studies that are reviewed herein. Already, approved indications have been achieved for doxorubicin against Kaposi’s sarcoma and ovarian cancers, and for daunorubicin against Kaposi’s sarcoma. The three compounds vary widely in their pharmacology, and these differences may contribute to their preferential localization into certain tumors. Additional indications for these liposomal encapsulated anthracyclines are likely to be established in the ensuing years.

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 and Recommended Reading

  1. Di Marco A, Gaetani M, Dorigotti L, et al.: Daunomycin: a new antibiotic of the rhodomycin group. Nature 1964, 201:706.

    Article  Google Scholar 

  2. Mathe G, Maral R: Second generation anthracyclines. In Anthracycline Antibiotics in Cancer Therapy. (Developments in Oncology, 10). Edited by Muggia FM, Young CW, Carter SK. The Hague: Martinus Nijhoff Publishers; 1982:190–204.

    Google Scholar 

  3. Di Marco A, Gaetani M, Scarpinato BM: Adriamycin (NSC-123, 127): a new antibiotic with antitumor activity. Cancer Chemother Rep 1969, 53:33–37.

    PubMed  Google Scholar 

  4. Sandberg JS, Howsden FL, Di Marco A, Goldin A: Comparison of the antileukemic effect in mice of adriamycin (NSC-123127) with daunomycin (NSC-82151). Cancer Chemother Rep 1970, 54:1–7.

    PubMed  CAS  Google Scholar 

  5. Bonadonna G, Monfardini S, DeLena M, et al.: Phase I and preliminary phase II evaluation of Adriamycin (NSC123127). Cancer Res 1970, 30:2572–2582.

    PubMed  CAS  Google Scholar 

  6. Tan C, Tasaka H, Yu KP, et al.: Daunomycin, an antitumor antibiotic, in the treatment of neoplastic disease. Cancer 1967, 20:333–353.

    Article  PubMed  CAS  Google Scholar 

  7. Boiron M, Jacquillat C, Weil M, et al.: Traitement des leucemies aigues granulocytaires par la rubidomycine [in French]. Pathol Biol (Paris) 1967, 15:921–924.

    CAS  Google Scholar 

  8. Blum R, Carter SK: Adriamycin: a new anticancer drug with significant clinical activity. Ann Intern Med 1974, 80:249–259.

    PubMed  CAS  Google Scholar 

  9. Benjamin RS: Adriamycin and other anthracycline antibiotics under study in the United States. In Antitumor Antibiotics (Recent Results in Cancer Research, 60). Edited by Carter SK, Umezawa H, Douros J, Sakurai Y. Berlin: Springer-Verlag,; 1978:230–240.

    Google Scholar 

  10. Poste G, Papahadjopoulos D: Lipid vesicles as carriers for introducing materials into cultured cells: influence of vesicle lipid composition on mechanism(s) of vesicle incorporation into cells. Proc Natl Acad Sci U S A 1976, 73:1603–1607.

    Article  PubMed  CAS  Google Scholar 

  11. Rahman A, Goldin A, Schein P: Pharmacologic and therapeutic characteristics of anthracycline liposome preparation. In Anthracycline Antibiotics in Cancer Therapy. (Developments in Oncology, 10). Edited by Muggia FM, Young CW, Carter SK. The Hague: Martinus Nijhoff Publishers; 1982:254–273.

    Google Scholar 

  12. Rogers KE, Forssen EA, Tokes ZA: Alternative methods of drug delivery. In Anthracycline Antibiotics in Cancer Therapy (Developments in Oncology, 10). Edited by Muggia FM, Young CW, Carter SK. The Hague: Martinus Nijhoff Publishers; 1982:282–291.

    Google Scholar 

  13. Rahman A, Treat J, Roth JK, et al.: A phase I clinical trial and pharmacokinetic evaluation of liposome-encapsulated doxorubicin. J Clin Oncol 1990, 8:1093–1100.

    PubMed  CAS  Google Scholar 

  14. Treat J, Greenspan A, Forst D, et al.: Antitumor activity of liposome encapsulated in doxorubicin in advanced breast cancer: a phase II study. J Natl Cancer Inst 1990, 82:1706–1710.

    Article  PubMed  CAS  Google Scholar 

  15. Henney JE, Von Hoff DD, Rozencweig M, Muggia FM: Thrombophlebitic potential of intravenous cytotoxic agents. Drug Intell Clin Pharmacol 1977, 11:266–267.

    Google Scholar 

  16. Ogawa M, Muggia FM, Rozencweig M: Adriamycin: Its Expanding Role in Cancer Treatment (International Congress Series). Tokyo: Excerpta Medica; 1984.

    Google Scholar 

  17. Muggia FM, Green MD, Speyer JL: Cancer Treatment and the Heart. Baltimore: Johns Hopkins University Press; 1992.

    Google Scholar 

  18. Launchbury AP, Habboubi N: Epirubicin and doxorubicin: a comparison of their characteristics, therapeutic activity and toxicity. Cancer Treat Rev 1993, 19:197–228.

    Article  PubMed  CAS  Google Scholar 

  19. Rahman A, Fumagalli A, Goodman A, Schein PS: Potential of liposomes to ameliorate anthracyccline-induced cardiotoxicity. Semin Oncol 1984, 11(suppl 3):45–48.

    PubMed  CAS  Google Scholar 

  20. Woodle MC, Storm G: Long Circulating Liposomes: Old Drugs, New Therapeutics. Berlin: Springer-Verlag and Landes Bioscience; 1998.

    Google Scholar 

  21. Matsumura Y, Maeda H: A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent SMANCS. Cancer Res 1986, 56:6387–6392.

    Google Scholar 

  22. Gill PS, Espina BM, Muggia F, et al.: Phase I/II clinical and pharmacokinetic evaluation of liposomal daunorubicin. J Clin Oncol 1995, 13:996–1003.

    PubMed  CAS  Google Scholar 

  23. Guaglianone P, Chan K, DelaFlor-Weiss E, et al.: Phase I and pharmacologic study of liposomal daunorubicin (DaunoXome). Invest New Drugs 1994, 12:103–110.

    Article  PubMed  CAS  Google Scholar 

  24. Gabizon A, Catane R, Uziely B, et al.: Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 1994, 54:987–992.

    PubMed  CAS  Google Scholar 

  25. Cowens JW, Creaven PJ, Greco WR, et al.: Initial clinical (phase I) trial of TLC D-99 (doxorubicin encapsulated in liposomes). Cancer Res 1993, 53:2796–2802.

    PubMed  CAS  Google Scholar 

  26. Booser D, Esparza-Guerra L, Zou Y, et al.: Liposomal annamycin. Phase I clinical and pharmacological study [abstract]. Proc ASCO 1997, 16:762.

    Google Scholar 

  27. Proffit RT, Williams LE, Presant CA, et al.: Tumor imaging potental of liposomes loaded with In-111-NTA: biodistribution in mice. J Nucl Med 1983, 24:45–51.

    Google Scholar 

  28. Northfelt DW, Martin FJ, Working P, et al.: Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi’s sarcoma. J Clin Pharmacol 1996, 36:55–63.

    PubMed  CAS  Google Scholar 

  29. Shapiro CL, Ervin T, Welles L, et al.: Phase II trial of high-dose liposome-encapsulated doxorubicin with granulocyte colony-stimulating factor in metastatic breast cancer: TLC D-99 Study Group. J Clin Oncol 1999, 17:1435–1441. A key paper in demonstrating the limitation of dose-intensifying classical liposomes.

    PubMed  CAS  Google Scholar 

  30. Krigel RL, Slywotzky CM, Lonberg M, et al.: Treatment of epidemic Kaposi’s sarcoma with a combination of interferonalpha-2b and etoposide. J Biol Respir Modif 1988, 7:359–364.

    CAS  Google Scholar 

  31. Gill PS, Wernz J, Scadden DT, et al.: Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi’s sarcoma. J Clin Oncol 1996, 14:2353–2364.

    PubMed  CAS  Google Scholar 

  32. Northfelt DW: Liposomal anthracycline chemotherapy in the treatment of AIDS-related Kaposi’s sarcoma. Oncology 1997, 10(suppl 11):21–32.

    Google Scholar 

  33. Volm MD, Wernz J: Patients with advanced AIDS-related Kaposi’s sarcoma (EKS) no longer require systemic therapy after introduction of effective antiretroviral therapy [abstract]. Proc ASCO 1997, 16:46a.

    Google Scholar 

  34. Cheung TW, Remick SC, Azarnia N, et al.: AIDS-related Kaposi’s sarcoma: a phase II study of liposomal doxorubicin: the TLC D-99 Study Group. Clin Cancer Res 1999, 5:3432–3437.

    PubMed  CAS  Google Scholar 

  35. Valero V, Buzdar AU, Theriault RL, et al.: Phase II trial of liposome-encapsulated doxorubicin, cyclophosphamide, and fluorouracil as first-line therapy in patients with metastatic breast cancer. J Clin Oncol 1999, 17:1425–1434.

    PubMed  CAS  Google Scholar 

  36. Ranson MR, Carmichael J, O’Byrne J, et al.: Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol 1996, 15:1385–1391.

    Google Scholar 

  37. Lyass O, Uziely B, Ben-Yosef M, et al.: Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer 2000, 89:1027–1047. A key paper linking pharmacology to specific toxicities observed with varied schedules of Doxil.

    Article  Google Scholar 

  38. Torri V, Harper PG, Colombo N, et al.: Paclitaxel and cisplatin in ovarian cancer [letter]. J Clin Oncol 2000, 18:2349.

    PubMed  CAS  Google Scholar 

  39. Delgado G, Potkul RK, Treat JA, et al.: A Phase I/II study of intraperitoneally administered doxorubicin entrapped in cardiolipin liposomes in patients with ovarian cancer. Am J Obstet Gynecol 1989, 160:812–817.

    PubMed  CAS  Google Scholar 

  40. Muggia FM, Hainsworth JD, Jeffers S, et al.: Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 1996, 15:987–993. This is the original description of the activity of Doxil in ovarian cancer, using a phase II open-label design and standard criteria of response.

    Google Scholar 

  41. Gordon AN, Aranai CO, Rose PG, et al.: Phase II study of liposomomal doxorubicin in platinum-and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol 2000, 18:3093–3100.

    PubMed  CAS  Google Scholar 

  42. Gordon AN, Fleagle JT, Parkin DE, et al.: Interim analysis of a phase III randomized trial of Doxil/Caelyx (D) versus topotecan (T) in the treatment of patients with relapsed ovarian cancer [abstract]. Proc ASCO 2000, 19:1504.

    Google Scholar 

  43. Krishna R, St-Louis M, Mayer LD: Increased intracellular drug accumulation and complete chemosensitization achieved in multidrug-resistant solid tumors by coadministering valspodar (PSC 833) with sterically stabilized liposomal doxorubicin. Int J Cancer 2000, 85:131–141. Report on a potentially important strategy to be utilized in combination with liposomes.

    Article  PubMed  CAS  Google Scholar 

  44. Tulpule A, Rarick MU, Kolitz J, et al.: Liposomal daunorubicin (Daunoxome) is active in the treatment of relapsed/refractory low-grade and intermediate-grade non-Hodgkin’s lymphoma (NHL) [abstract]. Blood 1998, 92(suppl 1):4036.

    Google Scholar 

  45. Flinn IW, Goodman SN, Post L, et al.: A dose-finding study of liposomal daunorubicin with CVP (COP-X) in advanced NHL. Ann Oncol 2000, 11:691–695.

    Article  PubMed  CAS  Google Scholar 

  46. Pratt G, Wiles ME, Rawstrom AC, et al.: Liposomal daunorubicin: in vitro and in vivo efficacy in multiple myeloma. Hematol Oncol 1998, 16:47–55.

    Article  PubMed  CAS  Google Scholar 

  47. Wollina U, Graefe T, Karte K: Treatment of relapsing or recalcitrant cutaneous T-cell lymphoma with pegylated liposomal doxorubicin. J Am Acad Dermatol 2000, 42:40–46.

    Article  PubMed  CAS  Google Scholar 

  48. Garcia AA, Kempf RA, Rogers M, Muggia FM: A phase II study of doxil (lipsomal doxorubicin): lack of activity in poor prognosis soft tissue sarcomas. Ann Oncol 1998, 9:1131–1133.

    Article  PubMed  CAS  Google Scholar 

  49. Baas P, van Meerbeeck J, Groen H, et al.: Caelyx in malignant mesothelioma: a phase II EORTC study. Ann Oncol 2000, 11:697–700.

    Article  PubMed  CAS  Google Scholar 

  50. Uziely B, Jeffers S, Isaacson R, et al.: Liposomal doxorubicin: antitumor activity and unique toxicity during two complementary phase I studies. J Clin Oncol 1995, 13:1777–1785.

    PubMed  CAS  Google Scholar 

  51. Safra T, Muggia F, Jeffers S, et al.: Pegylated liposomal doxorubicin (Doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 2000, 11:1–5.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. New York University School of Medicine, 550 First Avenue, 10016, New York, NY, USA

    Franco M. Muggia MD

Authors
  1. Franco M. Muggia MD
    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

Muggia, F.M. Liposomal encapsulated anthracyclines: new therapeutic horizons. Curr Oncol Rep 3, 156–162 (2001). https://doi.org/10.1007/s11912-001-0016-5

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-001-0016-5

Keywords

Search

Navigation