Combining Antiangiogenic Drugs with Vascular Disrupting Agents Rationale and Mechanisms of Action

摘要: A highly reproducible characteristic of vascular disrupting agent (VDA)-mediated anti-tumor therapy is the retention a rim viable tumor tissue surrounding much larger central mass necrotic within days therapy. Repopulation from subsequently compromises striking initial effect frequently caused by VDA treatment. The repopulation process driven in part robust angiogenesis, which therefore constitutes compelling rationale for combining with an antiangiogenic drug. In this regard, we have found that angiogenesis after can be driven, at least part, rapid systemic host response treatment itself, namely, induction hours mobilization bone marrow-derived cells (BMDCs) including circulating endothelial progenitor (CEPs). These migrate to drug treated and heavily colonize remaining rim. This appears high levels growth factors, G-CSF SDF-1. homing CEPs blunted prior or concurrent administration such as anti-VEGF receptor 2 antibodies – results enhanced overall activity, e.g. greater necrosis, smaller increased survival times. addition effect, more potent ‘local’ may also obtained adding result apoptosis associated vasculature. Preliminary clinical trial suggest combination has promising activity without significant increases toxicity, moreover, indicate some preclinical findings, VDA-induced elevations VEGF, are observed patients well.