MAZ51, an indolinone that inhibits endothelial cell and tumor cell growth in vitro, suppresses tumor growth in vivo.
We have recently described MAZ51, an indolinone that blocks the ligand-induced autophosphorylation of VEGFR-3, a receptor tyrosine kinase that plays a central role in the regulation of lymphangiogenesis. Here we show that MAZ51 is able to block the proliferation of VEGFR-3-expressing human endothelial cells and is less potently able to induce their apoptosis. MAZ51 also inhibits the proliferation and induces the apoptosis of a variety of non-VEGFR-3-expressing tumor cell lines. These data suggest that MAZ51 blocks the activity of tyrosine kinases in addition to VEGFR-3. In vivo, MAZ51 significantly inhibits the growth of rat mammary carcinomas. These data establish MAZ51 as a compound with antitumor properties that inhibits tumor growth directly and also indirectly by interfering with tumor-host interactions.
Kirkin
Vladimir
V
Forschungszentrum Karlsruhe, Institut für Toxikologie und Genetik, Karlsruhe, Germany.
Thiele
Wilko
W
Baumann
Petra
P
Mazitschek
Ralph
R
Rohde
Katrin
K
Fellbrich
Guido
G
Weich
Herbert
H
Waltenberger
Johannes
J
Giannis
Athanassios
A
Sleeman
Jonathan P
JP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D042583:Lymphangiogenesis / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D009281:Naphthalenes / Q000494:pharmacology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors*
C441602:3-(4-dimethylamino-naphthalen-1-ylmethylene)-1,3-dihydro-indol-2-one; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007211:Indoles; D009281:Naphthalenes; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D020797:Receptor, Platelet-Derived Growth Factor beta; D040321:Vascular Endothelial Growth Factor Receptor-3