Targeting VEGF to Prevent Tumor Angiogenesis
Introduction Vascular endothelia growth factors (VEGFs, letter labeled VEGF-A through VEGF-D) are a collection of protein hormones with significant structural similarities which induce angiogenesis through interactions with the VEGF receptors (VEGFRs, three unique VEGFRs have been identified VEFR-A, VEGFR-B, and VEGFR-C). Because tumor size is limited by the rate at which nutrients are delivered and waste products removed, tu mor growth can be partially regulated by disrupting its vascular network.1, 2 The complex interplay between the production of these signaling molecules, tertiary effects, and the blood supply of the tumor creates and environment where many VEGF inhibiting drugs have multiple actions, which may or may not all be antitumorigenic.3 The body’s natural mechanisms for regulating angiogenesis produce VEGFs and VEGF inhibitors, usually in the form of microRNAs which bind to VEGF mRNA and prevent the translation of mRNA to active VEGF proteins. Presence of these naturally occurring anti-VEGF species is associate with positive patient outcomes.4 Most clinically used anti-VEGFs are tyrosine kinase inhibitors which are non-specific in their sites of action.5 Methods To test whether anti-VEGFs directly inhibit tumor growth or are merely correlated with tumor suppression, anti-VEGF microRNAs were injected into mice with zenograft esophageal cancer.4,6 Cancer progression was measured by weight, dimensions, changes in vasculature, and survival time. Similar tests were executed to probe the efficacy of tyrosine kinase inhibitors for therapeutic purposes. Results The introduction of anti-VEGF agents has been con-sistently shown to limit tumor size but not to eradicate tumors completely.7, 8 For mice on microRNA therapies, survival times increased by a factor of 2 and tumors decreased in volume by up to 80%.6 Small trials have shown that tyrosine kinase inhibitors have similar effects on humans and at least 9 are currently approved for use in humans by the FDA. Tumor resistance to anti-VEGF therapy has also been reported in mice and humans.9 Conclusions Anti-VEGFs have a significant place in oncology as adjunct therapies but are not suitable as stand-alone therapies.
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