PMID- 17121904
OWN - NLM
STAT- MEDLINE
DCOM- 20070206
LR  - 20211203
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 12
IP  - 22
DP  - 2006 Nov 15
TI  - Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 
      17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple 
      myeloma.
PG  - 6826-35
AB  - PURPOSE: The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin 
      (mTOR) pathway and the heat shock protein family are up-regulated in multiple 
      myeloma and are both regulators of the cyclin D/retinoblastoma pathway, a 
      critical pathway in multiple myeloma. Inhibitors of mTOR and HSP90 protein have 
      showed in vitro and in vivo single-agent activity in multiple myeloma. Our 
      objective was to determine the effects of the mTOR inhibitor rapamycin and the 
      HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on multiple 
      myeloma cells. EXPERIMENTAL DESIGN: Multiple myeloma cell lines were incubated 
      with rapamycin (0.1-100 nmol/L) and 17-AAG (100-600 nmol/L) alone and in 
      combination. RESULTS: In this study, we showed that the combination of rapamycin 
      and 17-AAG synergistically inhibited proliferation, induced apoptosis and cell 
      cycle arrest, induced cleavage of poly(ADP-ribose) polymerase and 
      caspase-8/caspase-9, and dysregulated signaling in the phosphatidylinositol 
      3-kinase/AKT/mTOR and cyclin D1/retinoblastoma pathways. In addition, we showed 
      that both 17-AAG and rapamycin inhibited angiogenesis and osteoclast formation, 
      indicating that these agents target not only multiple myeloma cells but also the 
      bone marrow microenvironment. CONCLUSIONS: These studies provide the basis for 
      potential clinical evaluation of this combination for multiple myeloma patients.
FAU - Francis, Lanie K
AU  - Francis LK
AD  - University of Pittsburgh Cancer Institute, Division of Hematology/Oncology, 
      Department of Internal Medicine, Pittsburgh, Pennsylvania, USA.
FAU - Alsayed, Yazan
AU  - Alsayed Y
FAU - Leleu, Xavier
AU  - Leleu X
FAU - Jia, Xiaoying
AU  - Jia X
FAU - Singha, Ujjal K
AU  - Singha UK
FAU - Anderson, Judith
AU  - Anderson J
FAU - Timm, Michael
AU  - Timm M
FAU - Ngo, Hai
AU  - Ngo H
FAU - Lu, Ganwei
AU  - Lu G
FAU - Huston, Alissa
AU  - Huston A
FAU - Ehrlich, Lori A
AU  - Ehrlich LA
FAU - Dimmock, Elizabeth
AU  - Dimmock E
FAU - Lentzsch, Suzanne
AU  - Lentzsch S
FAU - Hideshima, Teru
AU  - Hideshima T
FAU - Roodman, G David
AU  - Roodman GD
FAU - Anderson, Kenneth C
AU  - Anderson KC
FAU - Ghobrial, Irene M
AU  - Ghobrial IM
LA  - eng
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Benzoquinones)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Lactams, Macrocyclic)
RN  - 4GY0AVT3L4 (tanespimycin)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Apoptosis/drug effects
MH  - Benzoquinones/administration & dosage/pharmacology/*therapeutic use
MH  - Bone Marrow Cells/drug effects
MH  - Cell Cycle/drug effects
MH  - Cell Differentiation/drug effects
MH  - Cell Line, Tumor
MH  - Drug Synergism
MH  - HSP90 Heat-Shock Proteins/*antagonists & inhibitors
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/metabolism
MH  - Lactams, Macrocyclic/administration & dosage/pharmacology/*therapeutic use
MH  - Models, Biological
MH  - Multiple Myeloma/*drug therapy
MH  - Neovascularization, Physiologic/drug effects
MH  - Osteoclasts/cytology/drug effects
MH  - Protein Kinases/*metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/administration & dosage/pharmacology/*therapeutic use
MH  - TOR Serine-Threonine Kinases
EDAT- 2006/11/24 09:00
MHDA- 2007/02/07 09:00
CRDT- 2006/11/24 09:00
PHST- 2006/11/24 09:00 [pubmed]
PHST- 2007/02/07 09:00 [medline]
PHST- 2006/11/24 09:00 [entrez]
AID - 12/22/6826 [pii]
AID - 10.1158/1078-0432.CCR-06-1331 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2006 Nov 15;12(22):6826-35. doi: 10.1158/1078-0432.CCR-06-1331.