Issues and challenges for antiangiogenic therapies

Angiogenesis is defined as the growth and proliferation of blood vessels from the existing vasculature, allowing a developing tissue to obtain the nutrients necessary to maintain growth. This fundamental mechanism underlies the processes of reproduction, development and repair and occurs in both normal and tumor tissues. Since this process is confined to rapidly growing tissues, and is quiescent in normal tissues, it was hypothesized by Folkman that any therapeutic intervention that inhibited angiogenesis would be relatively specific to tumors, sparing normal tissue. The mechanisms by which tumors induce angiogenesis are complex. Tumors rapidly outgrow the capacity of the vasculature in their host tissue to provide nutrition and oxygenation, and are inherently hypoxic. In response to hypoxia, they produce a number of potent protein-mediators that stimulate the growth of new blood vessels. These angiogenic factors are not specific to tumors - they are produced by all tissues in response to hypoxia. Many of the mechanisms have been elucidated at a molecular level, and a number of ligands, receptors and signal-transduction pathways defined. Many of these represent potential targets for the development of novel therapeutic agents. Several drug candidates that target angiogenic mechanisms are currently being evaluated in breast cancer. The ultimate goal of all such development is to improve disease outcome, and to augment currently available therapies. However, the evaluation of these drug candidates in clinical studies is complex and requires a fundamental re-appraisal of conventional clinical trial methodology and the application of advanced bioscientific technology to facilitate understanding of the complex pharmacology that they may produce.