PMID- 16740688
OWN - NLM
STAT- MEDLINE
DCOM- 20060727
LR  - 20220317
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 11
DP  - 2006 Jun 1
TI  - Antiangiogenic potential of the Mammalian target of rapamycin inhibitor 
      temsirolimus.
PG  - 5549-54
AB  - Mammalian target of rapamycin (mTOR) is increasingly recognized as a master 
      regulator of fundamental cellular functions, whose deregulation may underlie 
      neoplastic transformation and progression. Hence, mTOR has recently emerged as a 
      promising target for therapeutic anticancer interventions in several human 
      tumors, including breast cancer. Here, we investigated the antiangiogenic 
      potential of temsirolimus (also known as CCI-779), a novel mTOR inhibitor 
      currently in clinical development for the treatment of breast cancer and other 
      solid tumors. Consistent with previous reports, sensitivity to 
      temsirolimus-mediated growth inhibition varied widely among different breast 
      cancer cell lines and was primarily due to inhibition of proliferation with 
      little, if any, effect on apoptosis induction. In the HER-2 gene-amplified breast 
      cancer cell line BT474, temsirolimus inhibited vascular endothelial growth factor 
      (VEGF) production in vitro under both normoxic and hypoxic conditions through 
      inhibition of hypoxia-stimulated hypoxia-inducible factor (HIF)-1alpha expression 
      and transcriptional activation. Interestingly, these effects were also observed 
      in the MDA-MB-231 cell line, independent of its inherent sensitivity to the 
      growth-inhibitory effects of temsirolimus. A central role for mTOR (and the 
      critical regulator of cap-dependent protein translation, eIF4E) in the regulation 
      of VEGF production by BT474 cells was further confirmed using a small interfering 
      RNA approach to silence mTOR and eIF4E protein expression. In addition to its 
      effect on HIF-1alpha-mediated VEGF production, temsirolimus also directly 
      inhibited serum- and/or VEGF-driven endothelial cell proliferation and 
      morphogenesis in vitro and vessel formation in a Matrigel assay in vivo. Overall, 
      these results suggest that antiangiogenic effects may substantially contribute to 
      the antitumor activity observed with temsirolimus in breast cancer.
FAU - Del Bufalo, Donatella
AU  - Del Bufalo D
AD  - Laboratory of Experimental Chemotherapy and Division of Medical Oncology A, 
      Regina Elena National Cancer Institute, Rome, Italy.
FAU - Ciuffreda, Ludovica
AU  - Ciuffreda L
FAU - Trisciuoglio, Daniela
AU  - Trisciuoglio D
FAU - Desideri, Marianna
AU  - Desideri M
FAU - Cognetti, Francesco
AU  - Cognetti F
FAU - Zupi, Gabriella
AU  - Zupi G
FAU - Milella, Michele
AU  - Milella M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 624KN6GM2T (temsirolimus)
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  - Angiogenesis Inhibitors/*pharmacology
MH  - Breast Neoplasms/*blood supply/*drug therapy/metabolism/pathology
MH  - Cell Growth Processes/drug effects
MH  - Cell Line, Tumor
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Humans
MH  - Neovascularization, Pathologic/drug therapy/metabolism
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Protein Kinases/metabolism
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Vascular Endothelial Growth Factor A/biosynthesis
EDAT- 2006/06/03 09:00
MHDA- 2006/07/28 09:00
CRDT- 2006/06/03 09:00
PHST- 2006/06/03 09:00 [pubmed]
PHST- 2006/07/28 09:00 [medline]
PHST- 2006/06/03 09:00 [entrez]
AID - 66/11/5549 [pii]
AID - 10.1158/0008-5472.CAN-05-2825 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Jun 1;66(11):5549-54. doi: 10.1158/0008-5472.CAN-05-2825.