Lack of Efficacy of Combined Antiangiogenic Therapies in Xenografted Human Melanoma

Antiangiogenic therapy is theoretically a promising anticancer approach but does not always produce significant tumor control. Combinations of antiangiogenic therapies are therefore being investigated as strategies to enhance clinical benefit. Common targets for angiogenic blockade include endothelial specific receptors, such as Tie2/Tek, which signal blood vessel stabilization via recruitment and maturation of pericytes. Here, we report on the effects of targeted Tie2 antiangiogenic therapy (TekdeltaFc) in combination with nontargeted metronomic cyclophosphamide (LDM CTX) (reported to also act in antiangiogenic fashion) in xenografted human melanoma. Individually, these therapies showed transient antitumor activity, but, in combination, there was no significant reduction in tumor growth. In addition, while TekdeltaFc caused the expected increased pericyte coverage in treated blood vessels, LDM CTX alone or in combination with TekdeltaFc resulted in increased levels of VEGF production. Collectively, our data highlight the complexity of molecular interactions that may take place when antiangiogenic regimens are combined.