PMID- 17533397
OWN - NLM
STAT- MEDLINE
DCOM- 20071127
LR  - 20220205
IS  - 0007-0920 (Print)
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Linking)
VI  - 97
IP  - 2
DP  - 2007 Jul 16
TI  - Inhibition of epidermal growth factor receptor signalling reduces hypercalcaemia 
      induced by human lung squamous-cell carcinoma in athymic mice.
PG  - 183-93
AB  - The purpose of this study was to evaluate the role of the epidermal growth factor 
      receptor (EGFR) in parathyroid hormone-related protein (PTHrP) expression and 
      humoral hypercalcaemia of malignancy (HHM), using two different human 
      squamous-cell carcinoma (SCC) xenograft models. A randomised controlled study in 
      which nude mice with RWGT2 and HARA xenografts received either placebo or 
      gefitinib 200 mg kg(-1) for 3 days after developing HHM. Effectiveness of therapy 
      was evaluated by measuring plasma calcium and PTHrP, urine cyclic AMP/creatinine 
      ratios, and tumour volumes. The study end point was at 78 h. The lung SCC lines, 
      RWGT2 and HARA, expressed high levels of PTHrP mRNA as well as abundant EGFR 
      protein, but very little erbB2 or erbB3. Both lines expressed high transcript 
      levels for the EGFR ligand, amphiregulin (AREG), as well as, substantially lower 
      levels of transforming growth factor-alpha (TGF-alpha), and heparin 
      binding-epidermal growth factor (HB-EGF) mRNA. Parathyroid hormone-related 
      protein gene expression in both lines was reduced 40-80% after treatment with 1 
      muM of EGFR tyrosine kinase inhibitor PD153035 and precipitating antibodies to 
      AREG. Gefitinib treatment of hypercalcaemic mice with RWGT2 and HARA xenografts 
      resulted in a significant reduction of plasma total calcium concentrations by 78 
      h. Autocrine AREG stimulated the EGFR and increased PTHrP gene expression in the 
      RWGT2 and HARA lung SCC lines. Inhibition of the EGFR pathway in two human SCC 
      models of HHM by an anilinoquinazoline demonstrated that the EGFR tyrosine kinase 
      is a potential target for antihypercalcaemic therapy.
FAU - Lorch, G
AU  - Lorch G
AD  - Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 
      43210, USA. lorch.2@osu.edu
FAU - Gilmore, J L
AU  - Gilmore JL
FAU - Koltz, P F
AU  - Koltz PF
FAU - Gonterman, R M
AU  - Gonterman RM
FAU - Laughner, R
AU  - Laughner R
FAU - Lewis, D A
AU  - Lewis DA
FAU - Konger, R L
AU  - Konger RL
FAU - Nadella, K S
AU  - Nadella KS
FAU - Toribio, R E
AU  - Toribio RE
FAU - Rosol, T J
AU  - Rosol TJ
FAU - Foley, J
AU  - Foley J
LA  - eng
GR  - R01 CA077911/CA/NCI NIH HHS/United States
GR  - AR45585/AR/NIAMS NIH HHS/United States
GR  - R01 AR045585/AR/NIAMS NIH HHS/United States
GR  - CA77911/CA/NCI NIH HHS/United States
GR  - T32 RR07073/RR/NCRR NIH HHS/United States
GR  - R21 DK067875/DK/NIDDK NIH HHS/United States
GR  - DK067875/DK/NIDDK NIH HHS/United States
GR  - K01 RR021879/RR/NCRR NIH HHS/United States
GR  - RR00168/RR/NCRR NIH HHS/United States
GR  - P51 RR000168/RR/NCRR NIH HHS/United States
GR  - K26 RR000168/RR/NCRR NIH HHS/United States
GR  - K01RR021879/RR/NCRR NIH HHS/United States
GR  - T32 RR007073/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20070529
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Areg protein, mouse)
RN  - 0 (EGF Family of Proteins)
RN  - 0 (Glycoproteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Parathyroid Hormone-Related Protein)
RN  - 0 (Quinazolines)
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.10.1 (Receptor, ErbB-3)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Amphiregulin
MH  - Animals
MH  - Antineoplastic Agents/*therapeutic use
MH  - Carcinoma, Squamous Cell/*complications/metabolism/pathology
MH  - Cell Line, Tumor
MH  - EGF Family of Proteins
MH  - ErbB Receptors/analysis/*antagonists & inhibitors/metabolism
MH  - Gefitinib
MH  - *Gene Expression Regulation, Neoplastic
MH  - Glycoproteins/analysis/metabolism
MH  - Humans
MH  - Hypercalcemia/*drug therapy/etiology/genetics
MH  - Intercellular Signaling Peptides and Proteins/analysis/metabolism
MH  - Lung Neoplasms/*complications/metabolism/pathology
MH  - Mice
MH  - Mice, Nude
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Parathyroid Hormone-Related Protein/*genetics
MH  - Quinazolines/*therapeutic use
MH  - RNA, Messenger/analysis/metabolism
MH  - Receptor, ErbB-2/analysis/genetics/metabolism
MH  - Receptor, ErbB-3/analysis/genetics/metabolism
MH  - Signal Transduction
MH  - Xenograft Model Antitumor Assays
PMC - PMC2360295
EDAT- 2007/05/30 09:00
MHDA- 2007/12/06 09:00
PMCR- 2008/07/16
CRDT- 2007/05/30 09:00
PHST- 2007/05/30 09:00 [pubmed]
PHST- 2007/12/06 09:00 [medline]
PHST- 2007/05/30 09:00 [entrez]
PHST- 2008/07/16 00:00 [pmc-release]
AID - 6603828 [pii]
AID - 10.1038/sj.bjc.6603828 [doi]
PST - ppublish
SO  - Br J Cancer. 2007 Jul 16;97(2):183-93. doi: 10.1038/sj.bjc.6603828. Epub 2007 May 
      29.