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Blood, 15 December 2004, Vol. 104, No. 13, pp. 4181-4187. Prepublished online as a Blood First Edition Paper on August 10, 2004; DOI 10.1182/blood-2004-03-1153. This Article Full Text (PDF) All Versions of this Article: 2004-03-1153v1 104/13/4181    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Frost, P. Articles by Lichtenstein, A. Search for Related Content PubMed PubMed Citation Articles by Frost, P. Articles by Lichtenstein, A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 30, 2004 Accepted July 14, 2004 In vivo anti-tumor effects of the mTOR inhibitor, CCI-779, against human multiple myeloma cells in a xenograft model Patrick Frost, Farhad Moatomed, Bao Hoang, Yijiang Shi, Joseph Gera, Huajun Yan, Philip Frost, Jay Gibbons, and Alan Lichtenstein* Department of Medicine and Pathology, UCLA-West Los Angeles VA Medical Center, Los Angeles, CA, USA Department of Medicine, UCLA-West Los Angeles VA Medical Center, Los Angeles, CA, USA Research, Wyeth-Ayerst, Pearl River, NY, USA * Corresponding author; email: alan.lichtenstein{at}med.va.gov. In vitro studies indicates therapeutic potential of mTOR inhibitors in treating multiple myeloma. To provide further support for this potential, we used the rapamycin analog, CCI-779, in a myeloma xenograft model. CCI-779, given as 10 intraperitoneal injections, induced significant, dose-dependent, anti-tumor responses against subcutaneous growth of 8226, OPM-2 and U266 cell lines. Effective doses of CCI-779 were associated with modest toxicity, only inducing transient thrombocytopenia and leukopenia. Immunohistochemical studies demonstrated the anti-tumor responses were associated with inhibition of proliferation and angiogenesis, induction of apoptosis and reduction in tumor cell size. Although CCI-779-mediated inhibition of the p70S6 kinase mTOR substrate was equal in 8226 and OPM-2 tumor nodules, OPM-2 tumor growth was considerably more sensitive to inhibition of proliferation, angiogenesis and induction of apoptosis. Furthermore, the OPM-2 tumors from treated mice were more likely to show a down-regulated expression of cyclin D1 and c-myc and upregulated p27 expression. As prior work suggested that heightened AKT activity in OPM-2 tumors might induce hypersensitivity to mTOR inhibition, we directly tested this by stably transfecting a constitutively active AKT allele into U266 cells. The in vivo growth of these later cells was remarkably more sensitive to CCI-779 than growth of control U266 cell. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Toward a rational combinaTORial therapy for multiple myeloma Helena Jernberg-Wiklund and Kenneth Nilsson Blood 2004 104: 3845-3846. [Full Text] [PDF] This article has been cited by other articles: A. S. Fung, L. Wu, and I. F. Tannock Concurrent and Sequential Administration of Chemotherapy and the Mammalian Target of Rapamycin Inhibitor Temsirolimus in Human Cancer Cells and Xenografts Clin. Cancer Res., September 1, 2009; 15(17): 5389 - 5395. [Abstract] [Full Text] [PDF] B. Hoang, A. Benavides, Y. Shi, P. Frost, and A. Lichtenstein Effect of autophagy on multiple myeloma cell viability Mol. Cancer Ther., July 1, 2009; 8(7): 1974 - 1984. [Abstract] [Full Text] [PDF] P. Frost, Y. Shi, B. Hoang, J. Gera, and A. Lichtenstein Regulation of D-cyclin translation inhibition in myeloma cells treated with mammalian target of rapamycin inhibitors: rationale for combined treatment with extracellular signal-regulated kinase inhibitors and rapamycin Mol. Cancer Ther., January 1, 2009; 8(1): 83 - 93. [Abstract] [Full Text] [PDF] M. Beldner, M. Jacobson, G. E. Burges, D. Dewaay, J. C. Maize Jr., and U. B. Chaudhary Localized Palmar Plantar Epidermal Hyperplasia: A Previously Undefined Dermatologic Toxicity to Sorafenib Oncologist, October 1, 2007; 12(10): 1178 - 1182. [Abstract] [Full Text] [PDF] H. Younes, X. Leleu, E. Hatjiharissi, A.-S. Moreau, T. Hideshima, P. Richardson, K. C. Anderson, and I. M. Ghobrial Targeting the Phosphatidylinositol 3-Kinase Pathway in Multiple Myeloma Clin. Cancer Res., July 1, 2007; 13(13): 3771 - 3775. [Abstract] [Full Text] [PDF] R. J. Motzer and R. M. Bukowski Targeted Therapy for Metastatic Renal Cell Carcinoma J. Clin. Oncol., December 10, 2006; 24(35): 5601 - 5608. [Abstract] [Full Text] [PDF] E. Peponi, E. Drakos, G. Reyes, V. Leventaki, G. Z. Rassidakis, and L. J. Medeiros Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma Am. J. Pathol., December 1, 2006; 169(6): 2171 - 2180. [Abstract] [Full Text] [PDF] L. K. Francis, Y. Alsayed, X. Leleu, X. Jia, U. K. Singha, J. Anderson, M. Timm, H. Ngo, G. Lu, A. Huston, et al. Combination Mammalian Target of Rapamycin Inhibitor Rapamycin and HSP90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin Has Synergistic Activity in Multiple Myeloma. Clin. Cancer Res., November 15, 2006; 12(22): 6826 - 6835. [Abstract] [Full Text] [PDF] D. Del Bufalo, L. Ciuffreda, D. Trisciuoglio, M. Desideri, F. 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