PMID- 20370683
OWN - NLM
STAT- MEDLINE
DCOM- 20100816
LR  - 20191027
IS  - 1873-5576 (Electronic)
IS  - 1568-0096 (Linking)
VI  - 10
IP  - 3
DP  - 2010 May
TI  - Inhibition of c-Met with the specific small molecule tyrosine kinase inhibitor 
      SU11274 decreases growth and metastasis formation of experimental human melanoma.
PG  - 332-42
AB  - The hepatocyte growth factor/scatter factor (HGF/SF) tyrosine kinase (TK) 
      receptor c-Met plays a crucial role in the development of the invasive phenotype 
      of tumors and thus represents an attractive candidate for targeted therapies in a 
      variety of malignancies, including human malignant melanoma (MM). In contrast to 
      what has been shown previously, we were not able to detect any genetic 
      alterations, either in the juxtamembrane- or in the TK-domain of c-Met, in the 
      studied MM cell lines. Nevertheless, c-Met was constitutively active in these 
      cell lines without exogenous HGF/SF stimulation. The active receptor was 
      localized to the adhesion sites of the cells. Addition of the c-Met TK inhibitor 
      SU11274 specifically decreased the phosphotyrosine signal at the focal adhesions 
      sites, which was accompanied by a decrease in cell proliferation as well as an 
      increase in apoptotic cells. In addition, non-apoptotic concentrations of SU11274 
      significantly reduced the in vitro migratory capacity of MM cells in the modified 
      Boyden-chamber assay. Administration of SU11274 significantly decreased primary 
      tumor growth as well as the capacity for liver colony formation of MM cells in 
      SCID mice. Our study provides the first evidence for an in vivo antitumor 
      activity of SU11274 in a human melanoma xenograft model, and suggests c-Met as a 
      valid target for the therapy of MM. Consequently, SU11274 treatment might 
      represent a useful strategy for controlling melanoma progression and metastasis 
      in patients with MM.
FAU - Kenessey, Istvan
AU  - Kenessey I
AD  - 2nd Institute of Pathology, Semmelweis University, Budapest, Hungary.
FAU - Keszthelyi, Magdolna
AU  - Keszthelyi M
FAU - Kramer, Z
AU  - Kramer Z
FAU - Berta, Judit
AU  - Berta J
FAU - Adam, Attila
AU  - Adam A
FAU - Dobos, Judit
AU  - Dobos J
FAU - Mildner, Michael
AU  - Mildner M
FAU - Flachner, Beata
AU  - Flachner B
FAU - Cseh, Sandor
AU  - Cseh S
FAU - Barna, Gabor
AU  - Barna G
FAU - Szokol, Balint
AU  - Szokol B
FAU - Orfi, Laszl
AU  - Orfi L
FAU - Keri, Gyorgy
AU  - Keri G
FAU - Dome, Balazs
AU  - Dome B
FAU - Klepetko, Walter
AU  - Klepetko W
FAU - Timar, J
AU  - Timar J
FAU - Tovari, J
AU  - Tovari J
LA  - eng
PT  - Journal Article
PL  - Netherlands
TA  - Curr Cancer Drug Targets
JT  - Current cancer drug targets
JID - 101094211
RN  - 0 
      (((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide))
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Indoles)
RN  - 0 (Piperazines)
RN  - 0 (Sulfonamides)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/*drug effects
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/*pharmacology
MH  - Focal Adhesions/drug effects/enzymology
MH  - Humans
MH  - Indoles/*pharmacology
MH  - Liver Neoplasms/*drug therapy/enzymology/secondary
MH  - Melanoma/*drug therapy/enzymology/pathology
MH  - Mice
MH  - Mice, SCID
MH  - Phosphorylation
MH  - Piperazines/*pharmacology
MH  - Proto-Oncogene Proteins c-met/*antagonists & inhibitors/metabolism
MH  - RNA Interference
MH  - Sulfonamides/*pharmacology
MH  - Time Factors
MH  - Transfection
MH  - Tyrosine
MH  - Xenograft Model Antitumor Assays
EDAT- 2010/04/08 06:00
MHDA- 2010/08/17 06:00
CRDT- 2010/04/08 06:00
PHST- 2009/05/12 00:00 [received]
PHST- 2010/03/27 00:00 [accepted]
PHST- 2010/04/08 06:00 [entrez]
PHST- 2010/04/08 06:00 [pubmed]
PHST- 2010/08/17 06:00 [medline]
AID - EPub-Abstract-CCDT-31 [pii]
AID - 10.2174/156800910791190184 [doi]
PST - ppublish
SO  - Curr Cancer Drug Targets. 2010 May;10(3):332-42. doi: 10.2174/156800910791190184.