Novel compounds with antiangiogenic and antiproliferative potency for growth control of testicular germ cell tumours.
BACKGROUND
Testicular germ cell tumour (TGCT) is the most common cause of death from solid tumours in young men and especially for platinum-refractory patients novel treatment approaches are urgently needed. Using an in silico screening approach for the detection of novel cancer drugs with inhibitory effects on the tyrosine kinase activity of growth factors (e.g., VEGFR, PDGFR), we identified two compounds (HP-2 and HP-14) with antiangiogenic and antiproliferative potency, which were evaluated in endothelial cell models and TGCT cells.


RESULTS
HP-2 and HP-14 effectively inhibited the growth of VEGFR-2-expressing TGCT cell lines (Tera-1, Tera-2 and 2102EP) and endothelial cell models, while they failed to supress the growth of VEGFR-2-lacking tumour cells. cDNA-microarrays revealed an inhibition of the expression of several growth factor receptors and related signal transduction molecules. Vascular endothelial growth factor (VEGF)-induced cell migration was also potently inhibited. Cell cycle-regulating proteins such as p21 and p27 were upregulated, leading to an S-phase arrest. Additional in vivo evaluations confirmed the antiangiogenic potency and good tolerability of the novel substances.


CONCLUSIONS
Our data show that the identified novel compounds inhibit the growth of TGCT cells and decrease angiogenic microvessel formation. The mode of action involves cell cycle arresting effects and changes in the expression pattern of several angiogenic genes. The novel compounds may qualify as new candidates for targeted treatment of TGCT and merit further evaluation.
Nitzsche
B
B
Department of Physiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Arnimallee 22, Berlin 14195, Germany.
Gloesenkamp
C
C
Schrader
M
M
Ocker
M
M
Preissner
R
R
Lein
M
M
Zakrzewicz
A
A
Hoffmann
B
B
Höpfner
M
M
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000473:pathology
D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases