PMID- 24771207
OWN - NLM
STAT- MEDLINE
DCOM- 20141209
LR  - 20211203
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Linking)
VI  - 135
IP  - 12
DP  - 2014 Dec 15
TI  - Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma 
      models.
PG  - 2770-82
LID - 10.1002/ijc.28933 [doi]
AB  - Mammalian target of rapamycin (mTOR) is a new promising oncological target. 
      However, most clinical studies reported only modest antitumor activity during 
      mTOR-targeted monotherapies, including studies in osteosarcomas, emphasizing a 
      need for improvement. We hypothesized that the combination with rationally 
      selected other therapeutic agents may improve response. In this study, we 
      examined the efficacy of the mTOR inhibitor temsirolimus combined with cisplatin 
      or bevacizumab on the growth of human osteosarcoma xenografts (OS-33 and OS-1) in 
      vivo, incorporating functional imaging techniques and microscopic analyses to 
      unravel mechanisms of response. In both OS-33 and OS-1 models, the activity of 
      temsirolimus was significantly enhanced by the addition of cisplatin (TC) or 
      bevacizumab (TB). Extensive immunohistochemical analysis demonstrated apparent 
      effects on tumor architecture, vasculature, apoptosis and the mTOR-pathway with 
      combined treatments. 3'-Deoxy-3'-(18) F-fluorothymidine ((18) F-FLT) positron 
      emission tomography (PET) scans showed a remarkable decrease in (18) F-FLT signal 
      in TC- and TB-treated OS-1 tumors, which was already noticeable after 1 week of 
      treatment. No baseline uptake was observed in the OS-33 model. Both 
      immunohistochemistry and (18) F-FLT-PET demonstrated that responses as determined 
      by caliper measurements underestimated the actual tumor response. Although (18) 
      F-FLT-PET could be used for accurate and early response monitoring for 
      temsirolimus-based therapies in the OS-1 model, we could not evaluate OS-33 
      tumors with this molecular imaging technique. Further research on the value of 
      the use of (18) F-FLT-PET in this setting in osteosarcomas is warranted. Overall, 
      these findings urge the further exploration of TC and TB treatment for 
      osteosarcoma (and other cancer) patients.
CI  - (c) 2014 UICC.
FAU - Fleuren, Emmy D G
AU  - Fleuren ED
AD  - Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, the 
      Netherlands.
FAU - Versleijen-Jonkers, Yvonne M H
AU  - Versleijen-Jonkers YM
FAU - Roeffen, Melissa H S
AU  - Roeffen MH
FAU - Franssen, Gerben M
AU  - Franssen GM
FAU - Flucke, Uta E
AU  - Flucke UE
FAU - Houghton, Peter J
AU  - Houghton PJ
FAU - Oyen, Wim J G
AU  - Oyen WJ
FAU - Boerman, Otto C
AU  - Boerman OC
FAU - van der Graaf, Winette T A
AU  - van der Graaf WT
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140505
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Dideoxynucleosides)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0Z5B2CJX4D (Fluorodeoxyglucose F18)
RN  - 2S9ZZM9Q9V (Bevacizumab)
RN  - 624KN6GM2T (temsirolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - PG53R0DWDQ (alovudine)
RN  - Q20Q21Q62J (Cisplatin)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Angiogenesis Inhibitors/administration & dosage
MH  - Animals
MH  - Antibodies, Monoclonal, Humanized/*administration & dosage
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Bevacizumab
MH  - Bone Neoplasms/*drug therapy
MH  - Cell Line, Tumor
MH  - Cisplatin/*administration & dosage
MH  - Dideoxynucleosides
MH  - Female
MH  - Fluorodeoxyglucose F18
MH  - Humans
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Osteosarcoma/*drug therapy
MH  - Positron-Emission Tomography
MH  - Protein Kinase Inhibitors/administration & dosage
MH  - Sirolimus/administration & dosage/*analogs & derivatives
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Tomography, X-Ray Computed
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - 18F-FLT-PET
OT  - bevacizumab
OT  - cisplatin
OT  - osteosarcoma
OT  - temsirolimus
EDAT- 2014/04/29 06:00
MHDA- 2014/12/15 06:00
CRDT- 2014/04/29 06:00
PHST- 2013/11/29 00:00 [received]
PHST- 2014/04/14 00:00 [accepted]
PHST- 2014/04/29 06:00 [entrez]
PHST- 2014/04/29 06:00 [pubmed]
PHST- 2014/12/15 06:00 [medline]
AID - 10.1002/ijc.28933 [doi]
PST - ppublish
SO  - Int J Cancer. 2014 Dec 15;135(12):2770-82. doi: 10.1002/ijc.28933. Epub 2014 May 
      5.