|
|
Blood, 15 May 2005, Vol. 105, No. 10, pp. 3995-4003.
Prepublished online as a Blood First Edition Paper on January 18, 2005; DOI 10.1182/blood-2004-09-3534.
 Previous Article | Next Article 
Submitted September 14, 2004
Accepted January 9, 2005
PD166326, a novel tyrosine kinase inhibitor, has greater anti-leukemic activity than imatinib in a murine model of chronic myeloid leukemia
Nicholas C Wolff, Darren R Veach, William P Tong, William G Bornmann, Bayard Clarkson, and Robert L Ilaria*
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Division of Hematology/Oncology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
* Corresponding author; email: robert.ilaria{at}utsouthwestern.edu.
Imatinib mesylate is highly effective in newly diagnosed chronic myeloid leukemia (CML), but BCR/ABL-positive progenitors persist in most imatinib-treated CML patients, indicating the need for novel therapeutic approaches. In this study, we have used the murine CML-like myeloproliferative disorder as a platform to characterize the pharmacokinetic, signal transduction, and anti-leukemic properties of PD166326, one of the most potent members of the pyridopyrimidine class of protein tyrosine kinase inhibitors. In mice with the CML-like disease, PD166326 rapidly inhibited Bcr/Abl kinase activity after a single oral dose, and demonstrated marked anti-leukemic activity in vivo. Seventy percent of PD166326-treated mice achieved a WBC less than 20 000/µL at necropsy, compared with only 8% of imatinib-treated animals. Further, two-thirds of PD166326-treated animals had complete resolution of splenomegaly, compared to none of the imatinib-treated animals. Consistent with its more potent anti-leukemic effect in vivo, PD166326 was also superior to imatinib in inhibiting the constitutive tyrosine phosphorylation of numerous leukemia cell proteins, including the src family member Lyn. PD166326 also prolonged the survival of mice with imatinib-resistant CML induced by the Bcr/Abl mutants P210/H396P and P210/M351T. Altogether, these findings demonstrate the potential of more potent Bcr/Abl inhibitors to provide more effective anti-leukemic activity. Clinical development of PD166326 or a related analogue may lead to more effective drugs for the treatment of de novo and imatinib-resistant CML.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
E. I. Lerma, V.-A. Nguyen, T. Wang, A. Tipping, J. V. Melo, D. Kufe, D. J. Austin, and A. Deisseroth
Novel compounds with antiproliferative activity against imatinib-resistant cell lines
Mol. Cancer Ther.,
February 1, 2007;
6(2):
655 - 666.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. Kantarjian, M. Talpaz, F. Giles, S. O'Brien, and J. Cortes
New Insights into the Pathophysiology of Chronic Myeloid Leukemia and Imatinib Resistance
Ann Intern Med,
December 19, 2006;
145(12):
913 - 923.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. von Bubnoff, P. W. Manley, J. Mestan, J. Sanger, C. Peschel, and J. Duyster
Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107)
Blood,
August 15, 2006;
108(4):
1328 - 1333.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Scherr, A. Chaturvedi, K. Battmer, I. Dallmann, B. Schultheis, A. Ganser, and M. Eder
Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML)
Blood,
April 15, 2006;
107(8):
3279 - 3287.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Aloisi, S. Di Gregorio, F. Stagno, P. Guglielmo, F. Mannino, M. P. Sormani, P. Bruzzi, C. Gambacorti-Passerini, G. Saglio, S. Venuta, et al.
BCR-ABL nuclear entrapment kills human CML cells: ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B
Blood,
February 15, 2006;
107(4):
1591 - 1598.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. L. Ilaria Jr.
Pathobiology of Lymphoid and Myeloid Blast Crisis and Management Issues
Hematology,
January 1, 2005;
2005(1):
188 - 194.
[Abstract]
[Full Text]
[PDF]
|
|
|
| |
