|
|
Blood, 15 May 2006, Vol. 107, No. 10, pp. 4063-4070.
Prepublished online as a Blood First Edition Paper on January 19, 2006; DOI 10.1182/blood-2005-09-3870.
 Previous Article | Next Article 
Submitted September 27, 2005
Accepted January 6, 2006
Synergistic activity of the proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletal targeted radiotherapy in an orthotopic model of multiple myeloma
Apollina Goel, Angela Dispenzieri, Susan M Geyer, Suzanne Greiner, Kah-Whye Peng, and Stephen J Russell*
Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, MN, USA
Division of Hematology and Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
Biostatistics, Mayo Clinic College of Medicine, Rochester, MN, USA
* Corresponding author; email: sjr{at}mayo.edu.
Multiple myeloma is a highly radiosensitive skeletal malignancy, but bone-seeking radionuclides have not yet found their place in disease management. We previously reported that the proteasome inhibitor PS-341 selectively sensitizes myeloma cells to the lethal effects of ionizing radiation. To extend these observations to an in vivo model, we combined PS-341 with the bone-seeking radionuclide 153-Sm-EDTMP. In vitro clonogenic assays demonstrated synergistic killing of myeloma cells exposed to both PS-341 and 153-Sm-EDTMP. Using the orthotopic, syngeneic 5TGM1 myeloma model, the median survivals of mice treated with saline, two doses of PS-341 (0.5 mg/kg), or a single non-myeloablative dose of 153-Sm-EDTMP (22.5 MBq) were 21, 22 and 28 days, respectively. In contrast, mice treated with combination therapy comprising two doses of PS-341 (0.5 mg/kg), one day prior to and one day following 153-Sm-EDTMP (22.5 MBq) showed a significantly prolonged median survival of 49 days (p < 0.0001). In addition to prolonged survival, this treatment combination yielded reduced clonogenicity of bone-marrow resident 5TGM1 cells, reduced serum myeloma-associated paraprotein levels, and better preservation of bone mineral density. Myelosuppresion, determined by peripheral blood cell counts and clonogenicity assays of hematopoietic progenitors, did not differ between animals treated with 153-Sm-EDTMP alone versus those treated with the combination of PS-341 plus 153-Sm-EDTMP. PS-341 is a potent, selective in vivo radiosensitizer that may substantially impact the efficacy of skeletal targeted radiotherapy in multiple myeloma.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
Z. Jagani, K. Song, J. L. Kutok, M. R. Dewar, A. Melet, T. Santos, A. Grassian, S. Ghaffari, C. Wu, R. Ren, et al.
Proteasome Inhibition Causes Regression of Leukemia and Abrogates BCR-ABL-Induced Evasion of Apoptosis in Part through Regulation of Forkhead Tumor Suppressors
Cancer Res.,
August 15, 2009;
69(16):
6546 - 6555.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Berenson, O. Yellin, R. Patel, H. Duvivier, Y. Nassir, R. Mapes, C. D. Abaya, and R. A. Swift
A Phase I Study of Samarium Lexidronam/Bortezomib Combination Therapy for the Treatment of Relapsed or Refractory Multiple Myeloma
Clin. Cancer Res.,
February 1, 2009;
15(3):
1069 - 1075.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kim, J. M. Brush, P. A. Watson, N. A. Cacalano, K. S. Iwamoto, and W. H. McBride
Epidermal Growth Factor Receptor vIII Expression in U87 Glioblastoma Cells Alters Their Proteasome Composition, Function, and Response to Irradiation
Mol. Cancer Res.,
March 1, 2008;
6(3):
426 - 434.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Goel, S. K. Carlson, K. L. Classic, S. Greiner, S. Naik, A. T. Power, J. C. Bell, and S. J. Russell
Radioiodide imaging and radiovirotherapy of multiple myeloma using VSV({Delta}51)-NIS, an attenuated vesicular stomatitis virus encoding the sodium iodide symporter gene
Blood,
October 1, 2007;
110(7):
2342 - 2350.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
