title: Activity of nintedanib in germ cell tumors.
abstract: Germ cell tumors (GCTs) are the most frequent malignancy in male patients between 15 and 45 years of age. Cisplatin-based chemotherapy shows excellent cure rates, but patients with cisplatin-resistant GCTs have a poor prognosis. Nintedanib (BIBF 1120, Vargatef) inhibits the receptor classes vascular endothelial growth factor receptor, platelet derived growth factor receptor, and fibroblast growth factor receptor, and has shown activity against many tumors, as well as in idiopathic lung fibrosis and bleomycin-induced lung injury. Here, we investigated the antineoplastic and antiangiogenic properties of nintedanib in cisplatin-resistant and cisplatin-sensitive GCT cells, both alone and in combination with classical cytotoxic agents such as cisplatin, etoposide, and bleomycin. The half-maximal inhibitory concentration (IC50) of nintedanib was 4.5 ± 0.43 μmol/l, 3.1 ± 0.45 μmol/l, and 3.6 ± 0.33 μmol/l in cisplatin-sensitive NTERA2, 2102Ep, and NCCIT cells, whereas the IC50 doses of the cisplatin-resistant counterparts were 6.6 ± 0.37 μmol/l (NTERA2-R), 4.5 ± 0.83 μmol/l (2102Ep-R), and 6.1 ± 0.41 μmol/l (NCCIT-R), respectively. Single treatment with nintedanib induced apoptosis and resulted in a sustained reduction in the capacity of colony formation in both cisplatin-sensitive and cisplatin-resistant GCT cells. Cell cycle analysis showed that nintedanib induced a strong G0/G1-phase arrest in all investigated cell lines. Combination treatment with cisplatin did not result in additive, synergistic, or antagonistic effects. The in-vivo activity was studied using the chorioallantoic membrane assay and indicated the antiangiogenic potency of nintedanib with markedly reduced microvessel density. Topical treatment of inoculated tumor plaques resulted in a significant reduction of the tumor size. This indicates that nintedanib might be a promising substance in the treatment of GCT.
authors.affiliation: aLaboratory of Experimental Oncology, Department of Oncology, Hematology, Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumor Center, University Hospital Hamburg-Eppendorf, Hamburg bInstitute of Physiology, Charité, Universitätsmedizin Berlin, Berlin, Germany cTumor and Breast Center ZeTuP, St. Gallen, Switzerland.
authors.forename: Gustav
authors.initials: G
authors.lastname: Steinemann
authors.forename: Christine
authors.initials: C
authors.lastname: Jacobsen
authors.forename: Mirjam
authors.initials: M
authors.lastname: Gerwing
authors.forename: Jessica
authors.initials: J
authors.lastname: Hauschild
authors.forename: Gunhild
authors.initials: G
authors.lastname: von Amsberg
authors.forename: Michael
authors.initials: M
authors.lastname: Höpfner
authors.forename: Bianca
authors.initials: B
authors.lastname: Nitzsche
authors.forename: Friedemann
authors.initials: F
authors.lastname: Honecker
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D001761:Bleomycin; D005047:Etoposide; C530716:nintedanib; D002945:Cisplatin