Tissue examination to monitor antiangiogenic therapy: A phase I clinical trial with endostatin

Purpose: The purpose of this study was to determine the effect of the angio genesis inhibitor endostatin on blood vessels in tumors and wound sites. Experimental Design: In a Phase I dose escalation study, cancer patients we re treated with daily infusions of human recombinant endostatin. Tumor biop sies were obtained prior to and 8 weeks after initiation of treatment. Bloo d vessel formation in nonneoplastic tissue was evaluated by creating a skin wound site on the arm with a punch biopsy device. The wound site was sampl ed with a second biopsy after a 7-day interval. This sequential biopsy proc edure was performed prior to and 3 weeks after initiation of endostatin tre atment. Vascular density, endothelial cell kinetics, and blood vessel matur ity were determined in tumor and skin wound samples. The ultrastructure of tumor blood vessels was examined by electron microscopy. Results: As expected, the tumors were of variable vascular density. Skin wo unding induced a vascular granulation tissue containing a high percentage o f proliferating endothelial cells. The proportion of immature blood vessels was high in tumors and in wound sites and low in normal skin. No statistic ally significant difference was detected between pretreatment and treatment samples of tumors and of skin wounds for any of the parameters tested. Conclusions: Endostatin treatment was not associated with any recognizable vascular changes in tumor samples and did not perturb wound healing at the doses and the treatment schedule used.