title: Anti-tumour activity of two novel compounds in cisplatin-resistant testicular germ cell cancer.
abstract: BACKGROUND
  Resistance to cisplatin-based chemotherapy is associated with poor prognosis in testicular germ cell cancer, emphasising the need for new therapeutic approaches. In this respect, the therapeutic concept of anti-angiogenesis is of particular interest. In a previous study, we presented two novel anti-angiogenic compounds, HP-2 and HP-14, blocking the tyrosine kinase activity of angiogenic growth factor receptors, such as vascular endothelial growth factor receptor-2 (VEGFR-2), and related signalling pathways in testicular cancer. In this study, we investigated the efficacy of these new compounds in platinum-resistant testicular germ cell tumours (TGCTs), in vitro and in vivo.
  
  
  RESULTS
  Drug-induced changes in cell proliferation of the cisplatin-sensitive TGCT cell line 2102EP and its cisplatin-resistant counterpart 2102EP-R, both expressing the VEGFR-2, were evaluated by crystal violet staining. Both compounds inhibited the growth of cisplatin-resistant TGCT cells in a dose-dependent manner. In combination experiments with cisplatin, HP-14 revealed additive growth-inhibitory effects in TGCT cells, irrespective of the level of cisplatin resistance. Anti-angiogenic effects of HP compounds were confirmed by tube formation assays with freshly isolated human umbilical vein endothelial cells. Using TGCT cells inoculated onto the chorioallantoic membrane of fertilised chicken eggs (chicken chorioallantoic membrane assay), the anti-angiogenic and anti-proliferative potency of the novel compounds was also demonstrated in vivo. Gene expression profiling revealed changes in the expression pattern of genes related to DNA damage detection and repair, as well as in chaperone function after treatment with both cisplatin and HP-14, alone or in combination. This suggests that HP-14 can revert the lost effectiveness of cisplatin in the resistant cells by altering the expression of critical genes.
  
  
  CONCLUSIONS
  The novel compound HP-14 effectively inhibits the growth of cisplatin-resistant TGCT cells and suppresses tumour angiogenesis. Thus, HP-14 may be an interesting new agent that should be further explored for TGCT treatment, especially in TGCTs that are resistant to cisplatin.
authors.affiliation: Institute of Physiology, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Nitzsche
authors.forename: C
authors.initials: C
authors.lastname: Gloesenkamp
authors.forename: M
authors.initials: M
authors.lastname: Schrader
authors.forename: B
authors.initials: B
authors.lastname: Hoffmann
authors.forename: F
authors.initials: F
authors.lastname: Zengerling
authors.forename: S
authors.initials: S
authors.lastname: Balabanov
authors.forename: F
authors.initials: F
authors.lastname: Honecker
authors.forename: M
authors.initials: M
authors.lastname: Höpfner
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002642:Chick Embryo; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D040301:Vascular Endothelial Growth Factor Receptor-2; D002945:Cisplatin