Measuring tumour vascular response to antivascular and antiangiogenic drugs

Abstract

The tumour vasculature is an attractive target for therapy because of its accessibility to blood-borne anticancer agents and the reliance of most tumour cells on an intact vascular supply for their survival. For convenience, therapeutic targeting of the tumour vasculature can be divided into antiangiogenic approaches, which target the process of new blood vessel development and antivascular approaches, which target the established tumour vasculature. Many agents are now in clinical trial for the treatment of cancer by these methods. The main aim of this article is to describe the vascular effects of some of these agents and identify suitable end-points for measuring efficacy in early clinical trials. For drugs which are active below their maximum tolerated dose (MTD), measurement of vascular end-points is required to determine the most effective dosing/scheduling protocols. In addition, many of the current and developing antiangiogenic agents have additional mechanisms of action unrelated to angiogenesis per se, requiring measurement of vascular end-points to understand their mechanisms of action. Measurement of tumour microvascular density (MVD) from tumour biopsies is a common method for assessing the efficacy of antiangiogenic drugs. The limitations of this method and alternative end-points, which take into account vascular function, are discussed. Pre-clinical data regarding tumour response to the antivascular agent combretastatin A-4 3-0-phosphate (CA-4-P) are discussed in the context of guiding clinical trial planning. Finally, the accessibility of vascular end-points for clinical imaging is addressed.