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Tissue Examination to Monitor Antiangiogenic Therapy

A Phase I Clinical Trial with Endostatin¹

Comprehensive Cancer Center [C. M., J. P. T., G. W., F. T. L., F. K., R. C., R. N., A. F.], Department of Pathology and Laboratory Medicine [L. A. S., A. F.], and Department of Biostatistics [R. C.], University of Wisconsin Madison, Wisconsin 53792; and Department of Obstetrics and Gynecology, University of Kiel, 24105 Germany [C. M.]

Purpose: The purpose of this study was to determine the effect of the angiogenesis inhibitor endostatin on blood vessels in tumors and wound sites.

Experimental Design: In a Phase I dose escalation study, cancer patients were treated with daily infusions of human recombinant endostatin. Tumor biopsies were obtained prior to and 8 weeks after initiation of treatment. Blood 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 sampled with a second biopsy after a 7-day interval. This sequential biopsy procedure was performed prior to and 3 weeks after initiation of endostatin treatment. Vascular density, endothelial cell kinetics, and blood vessel maturity 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 wounding induced a vascular granulation tissue containing a high percentage of proliferating endothelial cells. The proportion of immature blood vessels was high in tumors and in wound sites and low in normal skin. No statistically 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.

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