Vascular-targeting therapies for treatment of malignant disease.

Abstract

Tumor endothelium represents a valuable target for cancer therapy. The vasculature plays a critical role in the survival and continued growth of solid tumor masses; in addition, the inherent differences between tumor blood vessels and blood vessels associated with normal tissue make the tumor vasculature a unique target on which to base the design of novel therapeutics, which may allow highly selective treatment of malignant disease. Therapeutic strategies that target and disrupt the already formed vessel networks of growing tumors are actively being pursued. The goal of these approaches is to induce a rapid and catastrophic shutdown of the vascular function of the tumor so that blood flow is arrested and tumor cell death due to the resulting oxygen and nutrient deprivation and buildup of waste products occurs. Biologic approaches and small-molecule drugs that can be used to damage tumor vasculature have been identified. Physiologic, histologic/morphologic, and immunohistochemical assessments have demonstrated that profound disruption of the tumor vessel network can be observed minutes to hours after treatment. The small-molecule agents that have made the greatest advances in the clinical setting (5,6-dimethylxanthenone-4-acetic acid [DMXAA], combretastatin A4 disodium phosphate [CA4DP], and ZD6126) are the focus of the current review. Loss of patent blood vessels, decreased tumor blood flow, extensive necrosis, and secondary ischemia-induced tumor cell death have been well documented in a variety of preclinical tumor models treated with agents such as DMXAA, CA4DP, and ZD6126. The use of such agents in conjunction with irradiation and other chemotherapeutic agents has led to improved treatment outcomes. The targeting of tumors' supportive blood vessel networks could lead to improvements in cancer cure rates. It is likely that this approach will prove to be most efficacious when used in concert with conventional treatment strategies.