Target Inhibition in Antiangiogenic Therapy A Wide Spectrum of Selectivity and Specificity

Recent studies have revealed a previously unsuspected degree of vascular specialization within the host tissue and a tumor's microenvironment. The "vascular zip code" has been used to describe the unique expression of cell-surface molecules found in each vascular bed. Characterization of tumor blood vessels includes selective overexpression of a heterogenous group of proteins such as proteases, integrins, growth factor receptors, and proteoglycans. The process of angiogenesis consists of a "true cytokine storm," requiring many molecular events and biological steps. Antiangiogenic drugs may target a single critical kinase pathway or may interact with several nonspecific molecular targets via a process termed extended spectrum kinase inhibition. The latter strategy may lead to an absence of selectivity and specificity and may result in enhanced toxicities. In this review, we discuss recent developments in the pathogenesis of commonly observed adverse events and summarize new strategies that may ultimately improve efficacy and limit toxicity.