P194Novel compounds for antiangiogenic treatment of chemoresistant testicular germ cell cancer

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Abstract

Resistance to cisplatin-based chemotherapy is associated with poor prognosis for patients with testicular germ cell cancer emphasizing the need for new therapeutic approaches. In this respect, the therapeutic concept of antiangiogenesis has emerged as a promising practice. Here we investigated the suitability of two recently introduced novel compounds (HP-2 and HP-14) blocking the tyrosine kinase activity of angiogenic growth factor receptors such as VEGFR-2 for innovative treatment of cisplatin-resistant testicular germ cell tumors (TGCT).

Drug-induced changes in cell proliferation of the VEGFR-2 expressing cisplatin-sensitive or -resistant TGCT cell lines (2102 EP and 2102EP-R) were evaluated by impedance-based real time proliferation analysis (xCelligence). For in vivo studies TGCT cells were inoculated onto the chorioallantoic membrane of fertilized chicken eggs (CAM assay) and HP-induced inhibition of angiogenesis, tumor growth and viability was evaluated by stereomicroscopy and immunohistochemistry.

HP-2 and HP-14 dose-dependently inhibited the growth of both platinum-sensitive and −resistant TGCT cells by up to > 95%. In addition, combination experiments of HP-compounds together with cisplatin revealed additive growth inhibitory effects in cisplatin-sensitive TGCT cells. In vivo evaluations confirmed the antineoplastic potency of the novel compounds. Upon incuabtion with HP-2 or -14 a marked reduction in tumor volume and angiogenesis was observed in tumor bearing CAMs. Immunohistochemical analysis demonstrated a strongly reduced formation of tumor-feeding microvessels with significant morphological alterations, as compared to untreated microvessel networks.

Taken together the study demonstrates that the two novel antiangiogenic compounds HP-2 and HP-14 effectively suppress the growth of both platinum-sensitive and -resistant testicular germ cell cancers in vitro and also in vivo. The promising results merit further elucidation of the compounds as novel agents for targeted therapy of urologic cancers.

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