Skip to main content
SpringerLink
Log in

High Concentration of Daunorubicin and Daunorubicinol in Human Malignant Astrocytomas after Systemic Administration of Liposomal Daunorubicin

  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

The value of chemotherapy in patients with malignant astrocytoma remains controversial. In our laboratories in vitro experiments with organotypic spheroid cultures showed superior effectiveness of anthracyclines. Systemic administration did not provide in therapeutic concentrations so far. Because recent studies on Daunorubicin in liposomes in the treatment of Kaposi sarcoma have shown effectiveness with diminished systemic toxicity, we administered intravenously a single dose of Daunorubicin in liposomes in eight patients at different intervals prior to surgery (12–50 h). In samples taken from tumor, tumor-edge and where possible from adjacent brain, the levels of Daunorubicin and its active metabolite Daunorubicinol were assessed with high performance liquid chromatography. Here we report that high concentrations of Daunorubicin and Daunorubicinol were found in malignant gliomas after systemic administration of liposomal Daunorubicin.

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. Paoletti P, Butti G, Knerich R, Gaetani P, Assietti R: Chemotherapy for malignant gliomas of the brain: a review of ten-years experience. Acta Neurochir. (Wien.) 103(1-2): 35–46, 1990

    Google Scholar 

  2. Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP: Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 71(8): 2585–2597, 1993

    Google Scholar 

  3. Chang SM, Prados MD: Chemotherapy for gliomas. Curr Opin Oncol 7(3): 207–213, 1995

    Google Scholar 

  4. Neuwelt EA, Frenkel EP, Diehl J, Vu LH, Rapoport S, Hill S: Reversible osmotic blood-brain barrier disruption in humans: implications for the chemotherapy of malignant brain tumors. Neurosurgery 7(1): 44–52, 1980

    Google Scholar 

  5. Kelly PJ, Daumas-Duport C, Kispert DB, Kall BA, Scheithauer BW, Illig JJ: Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg 66(6): 865–874, 1987

    Google Scholar 

  6. Burger PC, Heinz ER, Shibata T, Kleihues, P: Topographic anatomy and CT correlations in the untreated glioblastoma multiforme. J Neurosurg 68(5): 698–704, 1988

    Google Scholar 

  7. Bobo H, Kapp JP, Vance R: Effect of intra-arterial cisplatin and 1,3-bis(2chloroethyl)-1-nitrosourea (BCNU) dosage on radiographic response and regional toxicity in malignant glioma patients: proposal of a new method of intra-arterial dosage calculation. J Neuro-Oncol 13(3): 291–299, 1992

    Google Scholar 

  8. Walter KA, Tamargo RJ, Olivi A, Burger PC, Brem H: Intratumoral chemotherapy. Neurosurgery 37(6): 1128–1145, 1995

    Google Scholar 

  9. Brem H, Ewend MG, Piantadosi S, Greenhoot J, Burger PC, Sisti M: The safety of interstitial chemotherapy with BCNU-loaded polymer followed by radiation therapy in the treatment of newly diagnosed malignant gliomas: phase I trial. J Neuro-Oncol 26(2): 111–123, 1995

    Google Scholar 

  10. Presant CA, Scolaro M, Kennedy P, Blayney DW, Flanagan B, Lisak J, Presant J: Liposomal daunorubicin treatment of HIV-associated Kaposi's sarcoma. Lancet 341(8855): 1242–1243, 1993

    Google Scholar 

  11. Gill PS, Wernz J, Scadden DT, Cohen P, Mukwaya GM, von Roenn JH, Jacobs M, Kempin S, Silverberg I, Gonzales G, Rarick MU, Myers AM, Shepherd F, Sawka C, Pike MC, Ross ME: Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol 14(8): 2353–2364, 1996

    Google Scholar 

  12. Kaaijk P, Troost D, de Boer OJ, Van Amstel P, Bakker PJ, Leenstra S, Bosch DA: Daunorubicin and doxorubicin but not BCNU have deleterious effects on organotypic multicellular spheroids of gliomas. Br J Cancer 74(2): 187–193, 1996

    Google Scholar 

  13. Beijnen JH, Meenhorst PL, van Gijn R, Fromme M, Rosing H, Underberg WJ: HPLC determination of doxorubicin, doxorubicinol and four aglycone metabolites in plasma of AIDS patients. J Pharm Biomed Anal 9(10-12): 995–1002, 1991

    Google Scholar 

  14. Balmaceda C: Advances in brain tumor chemosensitivity. Curr Opin Oncol 10(3): 194–200, 1998

    Google Scholar 

  15. Galanis E, Buckner JC, Burch PA, Schaefer PL, Dinapoli RP, Novotny PJ, Scheithauer BW, Rowland KM, Vukov AM, Mailliard JA, Morton RF: Phase II trial of nitrogen mustard, vincristine, procarbazine in patients with recurrent glioma: North Central Cancer Treatment Group results. J Clin Oncol 16(9): 2953–2958, 1998

    Google Scholar 

  16. Pech IV, Peterson K, Cairncross JG: Chemotherapy for brain tumors. Oncology (Huntingt) 12(4): 537–543, 547, 1998

    Google Scholar 

  17. Burton E and Prados M: New chemotherapy options for the treatment of malignant gliomas. Curr Opin Oncol 11(3): 157–161, 1999

    Google Scholar 

  18. von Holst H, Knochenhauer E, Blomgren H, Collins VP, Ehn L, Lindquist M, Noren G, Peterson C: Uptake of adriamycin in tumour and surrounding brain tissue in patients with malignant gliomas. Acta Neurochir (Wien) 104(1-2): 13–16, 1990

    Google Scholar 

  19. Siegal T, Horowitz A, Gabizon A: Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biodistribution and therapeutic efficacy. J Neurosurg 83(6): 1029–1037, 1995

    Google Scholar 

  20. Sharma US, Sharma A, Chau RI, Straubinger RM: Liposome-mediated therapy of intracranial brain tumors in a rat model. Pharm Res 14(8): 992–998, 1997

    Google Scholar 

  21. Nabors MW, Griffin CA, Zehnbauer BA, Hruban RH, Phillips PC, Grossman SA, Brem H, Colvin OM: Multidrug resistance gene (MDR1) expression in human brain tumors. J Neurosurg 75(6): 941–946, 1991

    Google Scholar 

  22. Krishna R, Mayer LD: Liposomal doxorubicin circumvents PSC 833-free drug interactions, resulting in effective therapy of multidrug-resistant solid tumors. Cancer Res 57(23): 5246–5253, 1997

    Google Scholar 

  23. Watts RG, Merchant RE: Cerebrovascular effects and tumor kinetics after a single intratumoral injection of human recombinant interleukin-2 alone or in combination with intravenous chemotherapy in a rat model of glioma. Neurosurgery 31(1): 89–98, 1992

    Google Scholar 

  24. Valtonen S, Timonen U, Toivanen P, Kalimo H, Kivipelto L, Heiskanen O, Unsgaard G, Kuurne T: Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 41(1): 44–48, 1997

    Google Scholar 

  25. Amantea MA, Forrest A, Northfelt DW, Mamelok R: Population pharmacokinetics and pharmacodynamics of pegylated-liposomal doxorubicin in patients with AIDSrelated Kaposi's sarcoma. Clin Pharmacol Ther 61(3): 301–311, 1997

    Google Scholar 

  26. Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R, Martin F, Huang A, Barenholz Y: Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54(4): 987–992, 1994

    Google Scholar 

  27. Nakazawa S, Itoh Y, Shimura T, Matsumoto M, Yajima K: [New management of brain neoplasms. 2. Local injection of adriamycin]. No Shinkei Geka 11(8): 821–827, 1983

    Google Scholar 

  28. Coukell AJ, Spencer CM: Polyethylene glycol-liposomal doxorubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of AIDS-related Kaposi's sarcoma. Drugs 53(3): 520–538, 1997

    Google Scholar 

  29. Forssen EA, Tokes, ZA: Use of anionic liposomes for the reduction of chronic doxorubicin-induced cardiotoxicity. Proc Natl Acad Sci USA 78(3): 1873–1877, 1981

    Google Scholar 

  30. Uziely B, Jeffers S, Isacson R, Kutsch K, Wei-Tsao D, Yehoshua Z, Libson E, Muggia FM, Gabizon A: Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies. J Clin Oncol 13(7): 1777–1785, 1995

    Google Scholar 

  31. van Hoesel QG, Steerenberg PA, Crommelin DJ, van Dijk A, van Oort W, Klein S, Douze JM, de Wildt DJ, Hillen FC: Reduced cardiotoxicity and nephrotoxicity with preservation of antitumor activity of doxorubicin entrapped in stable liposomes in the LOU/M Wsl rat. Cancer Res 44(9): 3698–3705, 1984

    Google Scholar 

  32. Rahman A, Treat J, Roh JK, Potkul LA, Alvord WG, Forst D, Woolley PV: A phase I clinical trial and pharmacokinetic evaluation of liposome-encapsulated doxorubicin. J Clin Oncol 8(6): 1093–1100, 1990

    Google Scholar 

  33. Pouna P, Bonoron-Adele S, Gouverneur G, Tariosse L, Besse P, Robert, J: Development of the model of rat isolated perfused heart for the evaluation of anthracycline cardiotoxicity and its circumvention. Br J Pharmacol 117(7): 1593–1599, 1996

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Graduate School of Neurosciences, Academic Medical Center, University of Amsterdam, The Netherlands

    Kees W. Albrecht, Philip C. de Witt Hamer, Sieger Leenstra & Andries D. Bosch

  2. Department of Medical Oncology, Graduate School of Neurosciences, Academic Medical Center, University of Amsterdam, The Netherlands

    Piet J.M. Bakker

  3. Department of Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands

    Jos H. Beijnen

  4. Department of (Neuro)Pathology, Graduate School of Neurosciences, Academic Medical Center, University of Amsterdam, The Netherlands

    Dirk Troost & Patricia Kaaijk

Authors
  1. Kees W. Albrecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip C. de Witt Hamer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sieger Leenstra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Piet J.M. Bakker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jos H. Beijnen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dirk Troost
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Patricia Kaaijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andries D. Bosch
    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

Albrecht, K.W., de Witt Hamer, P.C., Leenstra, S. et al. High Concentration of Daunorubicin and Daunorubicinol in Human Malignant Astrocytomas after Systemic Administration of Liposomal Daunorubicin. J Neurooncol 53, 267–271 (2001). https://doi.org/10.1023/A:1012287212388

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1012287212388

Search

Navigation