Angiogenesis and vascular targeting: relevance for hyperthermia.

The creation of a functional blood supply from the normal tissue vasculature via the process of angiogenesis is critical for the continued growth and development of solid tumours. This importance has led to the concept of targeting the tumour vasculature as a therapeutic strategy, and two major types of vascular targeting agents (VTAs) have developed; those that inhibit the angiogenic process--angiogenesis inhibiting agents (AIAs)--and those that specifically damage the already established neovasculature--vascular disrupting agents (VDAs). The tumour vasculature also plays a critical role in influencing the response to hyperthermia. Generally, the poorer the blood supply the better the heat effect, thus combining VTAs with heat would appear to be a logical approach. Numerous pre-clinical studies have now demonstrated the benefits of combining AIAs or VDAs with heat to improve tumour response. VDAs have also been shown to enhance thermoradiosensitisation, especially at mild hyperthermia temperatures. Although some enhancement of normal tissue response has been observed when VDAs are given with heat, the effects are always less than those seen in tumours, and no increased normal tissue reactions are seen when radiation, VDAs and heat are combined, thus a therapeutic benefit exists. These pre-clinical studies clearly encourage clinical trials with these combinations.