PMID- 21498540
OWN - NLM
STAT- MEDLINE
DCOM- 20110705
LR  - 20220129
IS  - 1535-5667 (Electronic)
IS  - 0161-5505 (Linking)
VI  - 52
IP  - 5
DP  - 2011 May
TI  - ErbB-2 blockade and prenyltransferase inhibition alter epidermal growth factor 
      and epidermal growth factor receptor trafficking and enhance (111)In-DTPA-hEGF 
      Auger electron radiation therapy.
PG  - 776-83
LID - 10.2967/jnumed.110.084392 [doi]
AB  - The intracellular distribution of Auger electron-emitting radiopharmaceuticals is 
      a determinant of cytotoxicity. However, the mechanisms by which these agents are 
      routed through the cell are ill understood. The aim of this study was to 
      investigate how trafficking of (111)In-labeled human epidermal growth factor 
      ((111)In-DTPA-hEGF) relates to that of the EGF receptor (EGFR) and whether 
      coadministration of agents that modulate EGFR signaling alters the efficacy of 
      (111)In-DTPA-hEGF. METHODS: The spatiotemporal interaction between 
      AlexaFluor488-EGF (AF488-EGF) and Cy3-conjugated anti-EGFR antibody 
      (Cy3-anti-EGFR) was studied in the breast cancer cell line MDA-MB-468 using 
      fluorescence resonance energy transfer and 2-photon fluorescence lifetime 
      imaging. (111)In internalization and nuclear fractionation assays were performed 
      to investigate the effect of the ErbB-2-blocking antibody trastuzumab and a 
      prenyltransferase inhibitor, L-778,123, on the subcellular localization of 
      (111)In-DTPA-hEGF in MDA-MB-468 (1.3 x 10(6) EGFR per cell; ErbB-2 negative) and 
      231-H2N (0.2 x 10(6) EGFR per cell; 0.4 x 10(5) ErbB-2 per cell) cell lines. The 
      cytotoxicity of (111)In-DTPA-hEGF (0-64 nM) plus trastuzumab (0-50 mug/mL) or 
      L-778,123 (0-22.5 muM) was measured using clonogenic assays in a panel of breast 
      cancer cell lines that express different levels of EGFR and ErB-2. Clonogenic 
      survival data were used to calculate combination indices. Tumor growth inhibition 
      was measured in vivo in 231-H2N xenograft-bearing mice treated with 
      (111)In-DTPA-hEGF plus trastuzumab or L-788,123. RESULTS: Using fluorescence 
      resonance energy transfer, we showed that EGF interacts with EGFR in the 
      cytoplasm and nucleus after internalization of the ligand-receptor complex in 
      MDA-MB-468 cells. Nuclear localization of (111)In-DTPA-hEGF is enhanced by 
      trastuzumab and L-788,123. Trastuzumab and L-788,123 sensitized 231-H2N cells to 
      (111)In-DTPA-hEGF. Nuclear localization and cytotoxicity of (111)In-DTPA-hEGF 
      were significantly increased in 231-H2N xenografts by cotreatment with L-788,123 
      (P < 0.0001). CONCLUSION: The therapeutic efficacy of (111)In-DTPA-hEGF is 
      increased through the coadministration of selected molecularly targeted drugs 
      that modulate EGFR signaling and trafficking.
FAU - Cornelissen, Bart
AU  - Cornelissen B
AD  - Department of Oncology, CRUK/MRC Gray Institute for Radiation Oncology and 
      Biology, University of Oxford, Oxford, United Kingdom.
FAU - Darbar, Sonali
AU  - Darbar S
FAU - Hernandez, Rebecca
AU  - Hernandez R
FAU - Kersemans, Veerle
AU  - Kersemans V
FAU - Tullis, Iain
AU  - Tullis I
FAU - Barber, Paul R
AU  - Barber PR
FAU - Smart, Sean
AU  - Smart S
FAU - Vojnovic, Borivoj
AU  - Vojnovic B
FAU - Reilly, Raymond
AU  - Reilly R
FAU - Vallis, Katherine A
AU  - Vallis KA
LA  - eng
GR  - A6245/CRUK_/Cancer Research UK/United Kingdom
GR  - MRC_/Medical Research Council/United Kingdom
GR  - C14521/A6245/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110415
PL  - United States
TA  - J Nucl Med
JT  - Journal of nuclear medicine : official publication, Society of Nuclear Medicine
JID - 0217410
RN  - 0 (111In-DTPA-human epidermal growth factor)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Imidazoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 2A2059P49U (L 778,123)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - 7A314HQM0I (Pentetic Acid)
RN  - EC 2.5.1.1 (Dimethylallyltranstransferase)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - P188ANX8CK (Trastuzumab)
SB  - IM
MH  - Active Transport, Cell Nucleus/drug effects
MH  - Animals
MH  - Antibodies, Monoclonal/pharmacology
MH  - Antibodies, Monoclonal, Humanized
MH  - Cell Line, Tumor
MH  - Cell Nucleus/drug effects/metabolism
MH  - Cell Proliferation/drug effects
MH  - Colony-Forming Units Assay
MH  - Dimethylallyltranstransferase/*antagonists & inhibitors
MH  - Electrons/*therapeutic use
MH  - Epidermal Growth Factor/*metabolism/pharmacokinetics
MH  - ErbB Receptors/*metabolism
MH  - Female
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - Mice
MH  - Pentetic Acid/*analogs & derivatives/metabolism/pharmacokinetics
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Protein Transport/drug effects
MH  - Receptor, ErbB-2/*antagonists & inhibitors
MH  - Signal Transduction/drug effects
MH  - Trastuzumab
EDAT- 2011/04/19 06:00
MHDA- 2011/07/06 06:00
CRDT- 2011/04/19 06:00
PHST- 2011/04/19 06:00 [entrez]
PHST- 2011/04/19 06:00 [pubmed]
PHST- 2011/07/06 06:00 [medline]
AID - jnumed.110.084392 [pii]
AID - 10.2967/jnumed.110.084392 [doi]
PST - ppublish
SO  - J Nucl Med. 2011 May;52(5):776-83. doi: 10.2967/jnumed.110.084392. Epub 2011 Apr 
      15.