Abstract
The blood–brain barrier is a major obstacle for the chemotherapeutic drugs to effectively reach primary or secondary brain tumours. Stealth® liposomal drugs are highly accumulated in tumoural tissues. In the present study we investigated the relative accumulation of99mTc-DTPA radiolabelled stealth® liposomal doxorubicin (Caelyx®) in 10 patients with metastatic brain tumours and five patients with brain glioblastoma undergoing radiotherapy. Patients with metastatic brain lesions were treated with 10 consecutive fractions of radiotherapy (whole brain, 3 Gy/fraction, day 1–12) followed by a booster dose of 9 Gy (3 Gy/fraction, day 21–23). Caelyx®, at a dose of 25 mg mg–2was given on day 1 and on day 21. Radiolabelled Caelyx® accumulation was 13–19 times higher in the glioblastomas and 7–13 times higher in the metastatic lesions, as compared to the normal brain. The drug accumulation in the tumoural areas was 40–60% of the accumulation in the bone marrow of the skull bones. The normal brain radioactivity was <4% of the bone marrow, confirming an important shielding effect of the blood–brain barrier in the normal but not in the tumoural tissue. Four of 10 patients with metastatic lesions showed a complete response in CT-scan performed 2 months following therapy. There was no severe toxicity related to radiotherapy or to chemotherapy noted. It is concluded that stealth® liposomal drugs selectively overcome the blood–brain barrier in the tumoural areas. The clinical importance of this observation is now under investigation. © 2000 Cancer Research Campaign
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Abe T, Hasegawa S, Taniguchi K, Yokomizo A, Kuwano T, Ono M, Mori T, Hori S, Kohno K and Kuwano M (1994) Possible involvement of multidrug-resistance-associated protein (MRP) gene expression in spontaneous drug resistance to vincristine, etoposide and adriamycin in human glioma cells. Int J Cancer 58: 860–864
Bonner JA and Lawrence TS (1990) Doxorubicin decreases the repair of radiation-induced DNA damage. Int J Radiat Biol 57: 55–64
Cobbs CS, Brenman JE, Aldape KD, Bredt DS and Israel MA (1995) Expression of nitric oxide synthase in human central nervous system tumors. Cancer Res 15: 727–730
Davis FG, Freels S, Grutsch J, Barlas S and Brem S (1998) Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: an analysis based on surveillance, epidemiology, and end results (SEER) data, 1973–1991. J Neurosurg 88: 1–10
Doolittle ND, Petrillo A, Bell S, Cummings P and Eriksen S (1998) Blood–brain barrier disruption for the treatment of malignant brain tumors: The National Program. J Neurosci Nurs 30: 81–90
Dvorak HF, Nagy JA, Dvorak JT and Dvorak AM (1988) Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am J Pathol 133: 95–109
Fine HA, Dear KB, Loeffler JS, Black PM and Canellos GP (1993) Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults [see comments]. Cancer 71: 2585–2597
Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R, Martin F, Huang A and Barenholz Y (1994) Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54: 987–992
Gumerlock MK, Belshe BD, Madsen R and Watts C (1992) Osmotic blood–brain barrier disruption and chemotherapy in the treatment of high grade malignant glioma: patient series and literature review. J Neurooncol 12: 33–46
Harrington KJ, Rowlinson-Busza G, Uster PS, Whittaker J and Stewart JSW (1998) Stealth® liposome encapsulated doxorubicin (SLED) and iododeoxyruridine (SLIIUDR) as radiation sensitizers in head and neck squamous cell cancer xenograft tumors (HNSCCXT). Proc Am Soc Clin Oncol 17: 230a
Jayson GC and Howell A (1996) Carcinomatous meningitis in solid tumours. Ann Oncol 7: 773–786
Khalifa A, Dodds D, Rampling R, Paterson J and Murray T (1997) Lipsomal distribution in malignant glioma: possibilities for therapy. Nucl Med Commun 18: 17–23
Koukourakis MI, Giatromanolaki A, Kakolyris S, O'Byrne KJ, Apostolikas N, Skarlatos J, Gatter K and Harris AL (1998) Different patterns of stromal and cancer cell thymidine phosphorylase reactivity in non-small cell lung cancer. Impact on neoangiogenesis and survival. Br J Cancer 77: 1696–1703
Koukourakis MI, Koukouraki S, Giatromanolaki A, Archimandritis SC, Skarlatos J, Beroukas K, Bizakis J, Retalis G, Karkavitsas N and Helidonis ES (1999) Stealth liposomal doxorubicin and conventionally fractionated radiotherapy in the treatment of locally advanced non-small cell lung and head and neck cancer. J Clin Oncol 17: 3512–3521
Lasic DD, Martin FJ, Gabizon A, Huang SK and Papahadjopoulos D (1991) Sterically stabilized liposomes: a hypothesis on the molecular origin of the extended circulation times. Biochim Biophys Acta 1070: 187–192
Leon SP, Folkerth RD and Black PM (1996) Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 77: 362–372
Miller PJ, Hassanein RS, Giri PG, Kimler BF, O'Boynick P and Evans RG (1990) Univariate and multivariate statistical analysis of high-grade gliomas: the relationship of radiation dose and other prognostic factors. Int J Radiat Oncol Biol Phys 19: 275–280
Nakagawa K, Aoki Y, Fujimaki T, Tago M, Terahara A, Karasawa K, Sakata K, Sasaki Y, Matsutani M and Akanuma A (1998) High-dose conformal radiotherapy influenced the pattern of failure but did not improve survival in glioblastoma multiforme. Int J Radiat Oncol Biol Phys 40: 1141–1149
Nelson DF, Curran WJ Jr, Scott C, Nelson JS, Weinstein AS, Ahmad K, Constine LS, Murray K, Powlis WD and Mohiuddin M (1993) Hyperfractionated radiation therapy and bis-chlorethyl nitrosourea in the treatment of malignant glioma – possible advantage observed at 72.0 Gy in 1.2 Gy BID fractions: report of the Radiation Therapy Oncology Group Protocol 8302. Int J Radiat Oncol Biol Phys 25: 193–207
Paridaens R (1998) Efficacy of paclitaxel or doxorubicin used as single agents in advanced breast cancer: a literature survey. Semin Oncol 25: 3–6
Plate KH and Risau W (1995) Angiogenesis in malignant gliomas. Glia 15: 339–347
Rahman A, Husain SR, Siddiqui J, Verma M, Agresti M, Center M, Safa AR and Glazer RI (1992) Liposome-mediated modulation of multidrug resistance in human HL-60 leukemia cells. J Natl Cancer Inst 84: 1909–1915
Riondel J, Jacrot M, Fessi H, Puisieux, and Potier, (1992) Effects of free and liposome-encapsulated taxol on two brain tumors xenografted into nude mice. In Vivo 6: 23–27
Sakayama K, Masuno H, Miyazaki T, Okumura H, Shibata T and Okuda H (1994) Existence of lipoprotein lipase in human sarcomas and carcinomas. Jpn J Cancer Res 85: 515–521
Sherman DM, Carabell SC, Belli JA and Hellman S (1982) The effect of dose rate and adriamycin on the tolerance of thoracic radiation in mice. Int J Radiat Oncol Biol Phys 8: 45–51
Shibata S, Ochi A and Mori K (1990) Liposome as carriers of cisplatin into central nervous system – experiments with 9L gliomas in rats. Neurol Med Chir 30: 242–245
Siegal T, Horowitz A and Gabizon A (1995) Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biosistribution and therapeutic efficacy. J Neurosurg 83: 1029–1037
Stan AC, Casares S, Radu D, Walter GF and Brumeanu TD (1999) Doxorubicin-induced cell death in highly invasive human gliomas. Anticancer Res 19: 941–950
Stewart S and Harrington KJ (1997) The biodistribution and pharmacokinetics of stealth liposomes in patients with solid tumors. Oncology 10: 33–37
Valdivieso M, Burgess MA, Ewer MS, Mackay B, Wallace S, Benjamin RS, Ali MK, Bodey GP and Freireich EJ (1984) Increased therapeutic index of weekly doxorubicin in the therapy of non-small cell lung cancer: a prospective, randomized study. J Clin Oncol 2: 207–214
Warren L, Jardillier JC, Malrska A and Akeli MG (1992) Increased accumulation of drugs in multidrug-resistant cells induced by liposomes. Cancer Res 52: 3241–3245
Working PK, Newsman MS, Huang SK, Mayhew E, Vaage J and Lasic DD (1994) Pharmacokinetics, biodistribution and therapeutic efficacy of doxorubicin encapsulated in stealth® liposomes (Doxil®). J Liposom Res 4: 667–687
World Health Organization (1979). Handbook for reporting results of cancer treatment, WHO Offset Publications: Geneva
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Koukourakis, M., Koukouraki, S., Fezoulidis, I. et al. High intratumoural accumulation of stealth® liposomal doxorubicin (Caelyx®) in glioblastomas and in metastatic brain tumours. Br J Cancer 83, 1281–1286 (2000). https://doi.org/10.1054/bjoc.2000.1459
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2000.1459
Keywords
This article is cited by
-
Synthesis, Characterization, and In Vivo Distribution of 99mTc Radiolabelled Docetaxel Loaded Folic Acid-Thiolated Chitosan Enveloped Liposomes
BioNanoScience (2023)
-
Multifunctional lipidic nanocarriers for effective therapy of glioblastoma: recent advances in stimuli-responsive, receptor and subcellular targeted approaches
Journal of Pharmaceutical Investigation (2022)
-
Anthracycline-induced cytotoxicity in the GL261 glioma model system
Molecular Biology Reports (2021)
-
Liposomal Irinotecan Accumulates in Metastatic Lesions, Crosses the Blood-Tumor Barrier (BTB), and Prolongs Survival in an Experimental Model of Brain Metastases of Triple Negative Breast Cancer
Pharmaceutical Research (2018)
-
Cancer nanomedicine: progress, challenges and opportunities
Nature Reviews Cancer (2017)