Combination of Antiangiogenic Therapy with Other Anticancer Therapies

The study of angiogenesis in malignant tumors has a long history of more than 200 years. Formal modern studies of tumor angiogenesis and the search for therapeutic antiangiogenic agents have progressed very rapidly over the past 30 years. First generation antiangiogenic agents were very important because they allowed the opportunity to validate the concepts that blocking angigoegenesis could be therapeutically important in cancer and that a role could be found for such molecules in combination therapeutic regimens for cancer. Through the 1970s and 1980s, investigators faced a dilemma regarding how to incorporate agents that “choked-off” the tumor blood supply into multi-component therapeutic regimens that had been developed empirically over many years. TNP470, a synthetic molecule derived from a fungal toxin, and minocycline, a tetracycline, were very useful in the preclinical studies that demonstrated that antiangiogenic therapy could enhance the activity to cytotoxic chemostherapy and radiation therapy. These fisrt generation molecules failed to reach clinical approval, but very quickly antiangiogenic kinase inhibitor and antiangiogenic antibodies, especially bevacizumab, demonstrated very similar effects in preclinical models and entered clinical trial. Returning to early observations, cytotoxic therapies administered in continuous low dose regimens can take best advantage of the toxicity of these molecules toward endothelial cells in ‘metronomic’ regimens. Most recently, large genomics efforts have been devoted to identifying differences between normal endothelium and tumor endothelium with a goal to define highly selective tumor endothelial targets for therapeutic attack. The antiangiogenic therapies that have become approved drugs are administered to patients as important components for combination tereatment regimens.