Low Dose Carboplatin Combined With Angiostatic Agents Prevents Metastasis in Human Testicular Germ Cell Tumor Xenografts

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Abstract
Purpose: Low dose chemotherapy combined with angiogenesis inhibitors has been shown to be more effective for experimental tumor treatment than chemotherapy alone. To our knowledge whether germ cell tumors could benefit from this treatment strategy remains to be evaluated. We examined the efficacy of angiostatic thrombospondin-1 (TSP-1), endostatin and combined angiostatic/low dose carboplatin in mice xenografted with human nonseminomatous germ cell tumor Materials and Methods: We monitored tumor progression and angiogenesis in the established model of human nonseminomatous germ cell tumor xenograft in 120 SCID mice using intravital video microscopy, immunocytochemistry and real-time polymerase chain reaction. Mice received TSP-1 (20 mg/kg daily) or endostatin (10 mg/kg daily) subcutaneously (via osmotic mini pumps) for 2 weeks starting 15 days after cancer cell grafting, carboplatin cycled twice (30 mg/kg intraperitoneally days 14 and 21 after cancer cell grafting), or a combination of carboplatin with TSP-1 or endostatin. Untreated, sham and tumor bearing mice treated with Ringer’s solution served as controls. Results: Primary tumor development was not affected in mice treated with TSP-1, endostatin or carboplatin alone. All animals had metastases at 6 months, while metastasis did not develop following the combination of carboplatin with TSP-1 or endostatin. This combined therapy suppressed tumor angiogenesis, enhanced apoptosis in tumor cells and decreased vascular endothelial growth factor-A tissue mRNA expression vs controls (p <0.05). Conclusions: These data indicate that angiostatic agents added to low dose carboplatin have the ability to suppress the progression of human germ cell tumor xenografts toward a metastatic phenotype. Therefore, this treatment strategy might be beneficial to prevent metastasis in germ cell tumors.