The contribution of bone marrow-derived circulating endothelial progenitor cells (CEPs) to tumor angiogenesis has been controversial, primarily because of their low numbers in blood vessels of untreated tumors. We show that treatment of tumor-bearing mice with vascular disrupting agents (VDAs) leads to an acute mobilization of CEPs, which home to the viable tumor rim that characteristically remains after such therapy. Disruption of this CEP spike by antiangiogenic drugs or by genetic manipulation resulted in marked reductions in tumor rim size and blood flow as well as enhanced VDA antitumor activity. These findings also provide a mechanistic rationale for the enhanced efficacy of VDAs when combined with antiangiogenic drugs.

BACKGROUND. 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. METHODS. 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. RESULTS. 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. CONCLUSIONS. 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. Cancer 2004;100:2491-9.

Doses of CA4P on a daily times five schedule of 52 to 65 mg/m2 were reasonably well-tolerated. The 52 mg/m2 dose is recommended for further study based on cumulative phase I experience with CA4P. Antitumor efficacy was observed, and the use of DCE-MRI provided a valuable noninvasive measure of the vascular effects of CA4P treatment.