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Blood, 15 December 2004, Vol. 104, No. 13, pp. 4188-4193.
Prepublished online as a Blood First Edition Paper on August 19, 2004; DOI 10.1182/blood-2004-06-2281.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma
Noopur Raje,
Shaji Kumar,
Teru Hideshima,
Kenji Ishitsuka,
Dharminder Chauhan,
Constantine Mitsiades,
Klaus Podar,
Steven Le Gouill,
Paul Richardson,
Nikhil C. Munshi,
David I. Stirling,
Joseph H. Antin, and
Kenneth C. Anderson
From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, VA Boston Healthcare System and Harvard Medical School, Boston, MA; the Division of Hematology, Mayo Clinic, Rochester, MN; and Celgene Corporation, Warren, NJ.
Previous studies have demonstrated the in vitro and in vivo activity of CC-5013 (Revlimid), an immunomodulatory analog (IMiD) of thalidomide, in multiple myeloma (MM). In the present study, we have examined the anti-MM activity of rapamycin (Rapamune), a specific mTOR inhibitor, combined with CC-5013. Based on the Chou-Talalay method, combination indices of less than 1 were obtained for all dose ranges of CC-5013 when combined with rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional chemotherapy. Moreover, the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), or adherence to bone marrow stromal cells (BMSCs). Combining rapamycin and CC-5013 induced apoptosis of MM cells. Differential signaling cascades, including the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3'-kinase/Akt kinase (PI3K/Akt) pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies, therefore, provide the framework for clinical evaluation of mTOR inhibitors combined with IMiDs to improve patient outcome in MM.
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