|
|
Blood, 15 August 2008, Vol. 112, No. 4, pp. 1005-1012.
Prepublished online as a Blood First Edition Paper on May 13, 2008; DOI 10.1182/blood-2008-02-140665.
 Previous Article | Next Article 
Submitted February 19, 2008
Accepted April 14, 2008
Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia
Kimmo Porkka*, Perttu Koskenvesa, Tuija Lundan, Johanna Rimpilainen, Satu Mustjoki, Richard Smykla, Robert Wild, Roger Luo, Montserrat Arnan, Benoit Brethon, Lydia Eccersley, Henrik Hjorth-Hansen, Martin Hoglund, Hana Klamova, Havar Knutsen, Suhag Parikh, Emmanuel Raffoux, Franz Gruber, Finella Brito-Babapulle, Herve Dombret, Rafael F. Duarte, Erkki Elonen, Ron Paquette, C Michel Zwaan, and Francis YF Lee
Hematology Research Unit, Biomedicum Helsinki, Helsinki, Finland
Departments of Clinical Chemistry and Medicine/Hematology, Helsinki University Central Hospital, Helsinki, Finland
HUSLAB, Department of Molecular Pathology, Helsinki University Central Hospital, Helsinki, Finland
North-Karelia Central Hospital, Joensuu, Finland
Bristol-Myers Squibb Research and Development, Princeton, NJ, United States
In Vivo Pharmacology, OSI Pharmaceuticals, Boulder, CO, United States
ICO-Hospital Duran i Reynals, Barcelona, Spain
Pediatric Hematology, Hopital Saint-Louis, Paris, France
Ealing Hospital, Middlesex, United Kingdom
St Olavs Hospital and Department of Molecular Medicine and Cancer Research, Norwegian University of Science and Technology, Trondheim, Norway
Uppsala University Hospital, Uppsala, Sweden
Institute of Hematology and Blood Transfusion, Prague, Czech Republic
Akershus University Hospital, Lorenskog, Norway
Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, NC, United States
Hopital Saint-Louis, Paris, France
University of Tromso, Tromso, Norway
Hematology Research Unit, Biomedicum Helsinki, Finland
UCLA, Los Angeles, United States
Pediatric Oncology, Erasmus MC, Rotterdam, Netherlands
* Corresponding author; email: kimmo.porkka{at}helsinki.fi.
Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses due to poor drug penetration through the blood-brain barrier. Imatinib and dasatinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph+ leukemia. Clinical dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclinical studies, dasatinib increased survival, while imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease was achieved with continued dasatinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in seven patients. In three additional patients, isolated CNS relapse occurred during dasatinib therapy and in two of them it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease, and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (NCT00108719) and CA180015 (NCT00110097).
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
Systemic dasatinib fails to prevent development of central nervous system progression in a patient with BCR-ABL unmutated Philadelphia chromosome–positive leukemia
- Ferdinando Frigeri, Manuela Arcamone, Luigia Luciano, Raffaele Di Francia, Fabrizio Pane, and Antonio Pinto
Blood 2009 113: 5028-5029.
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
S. Hu, Z. Chen, R. Franke, S. Orwick, M. Zhao, M. A. Rudek, A. Sparreboom, and S. D. Baker
Interaction of the Multikinase Inhibitors Sorafenib and Sunitinib with Solute Carriers and ATP-Binding Cassette Transporters
Clin. Cancer Res.,
October 1, 2009;
15(19):
6062 - 6069.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Chen, S. Agarwal, N. M. Shaik, C. Chen, Z. Yang, and W. F. Elmquist
P-glycoprotein and Breast Cancer Resistance Protein Influence Brain Distribution of Dasatinib
J. Pharmacol. Exp. Ther.,
September 1, 2009;
330(3):
956 - 963.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. H. Sikkema, S. H. Diks, W. F.A. den Dunnen, A. ter Elst, F. J.G. Scherpen, E. W. Hoving, R. Ruijtenbeek, P. J. Boender, R. de Wijn, W. A. Kamps, et al.
Kinome Profiling in Pediatric Brain Tumors as a New Approach for Target Discovery
Cancer Res.,
July 15, 2009;
69(14):
5987 - 5995.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. L. Wheeler, M. Iida, and E. F. Dunn
The Role of Src in Solid Tumors
Oncologist,
July 1, 2009;
14(7):
667 - 678.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Frigeri, M. Arcamone, L. Luciano, R. Di Francia, F. Pane, and A. Pinto
Systemic dasatinib fails to prevent development of central nervous system progression in a patient with BCR-ABL unmutated Philadelphia chromosome-positive leukemia
Blood,
May 14, 2009;
113(20):
5028 - 5029.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Tyler
Once-Daily Dasatinib for Treatment of Patients with Chronic Myeloid Leukemia
Ann. Pharmacother.,
May 1, 2009;
43(5):
920 - 927.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. S. Lagas, R. A.B. van Waterschoot, V. A.C.J. van Tilburg, M. J. Hillebrand, N. Lankheet, H. Rosing, J. H. Beijnen, and A. H. Schinkel
Brain Accumulation of Dasatinib Is Restricted by P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) and Can Be Enhanced by Elacridar Treatment
Clin. Cancer Res.,
April 1, 2009;
15(7):
2344 - 2351.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Hehlmann and S. Saussele
Treatment of chronic myeloid leukemia in blast crisis
Haematologica,
December 1, 2008;
93(12):
1765 - 1769.
[Full Text]
[PDF]
|
|
|
|
|
