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Reduction of Wound Angiogenesis in Patients Treated with BMS-275291, a Broad Spectrum Matrix Metalloproteinase Inhibitor¹

Departments of Medicine [A. C. L., J. R. R., J. M. G., D. A. C., H. I. H.], Biostatistics and Bioinformatics [D. Y.], Radiation Oncology [R. D. B., M. W. D.], Biomedical Engineering [B. K., F. Y.], and Pathology [A. D. P.], Duke University Medical Center, Durham, North Carolina 27710, and Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492 [J. S. H., S. T., K. M. W.]

Purpose: The purpose of this study was to evaluate the feasibility of incorporating a novel wound angiogenesis assay into a Phase I study of BMS-275291, a broad-spectrum matrix metalloproteinase inhibitor, and to determine whether the wound angiogenesis assay was able to detect the inhibition of angiogenesis in patients treated with BMS-275291.

Experimental Design: Before treatment began, a 4-mm skin biopsy was performed. The wound was imaged for 14 days. Treatment was started on day 0, and a separate 4-mm biopsy was performed 14 days later. The second wound was also imaged for 14 days. Wound angiogenesis was scored by two independent observers who were blinded to treatment status.

Results: The median times in days (95% confidence interval) to reach the target average vascular score (AVS) of 1.5 and 2.0 based on the data of Observer 1 were 3.7 (2.2–6.9) and 8.0 (5.0–10.0) pretreatment whereas on-treatment the values were 4.9 (3.7–8.0) and 9.3 (7.0–11.5), respectively. The delay in the median time to reach an AVS of 1.5 was 1.2 days or a 32% reduction when comparing pretreatment with on-treatment (P = 0.06). For the target AVS of 2.0 the delay in the median time pretreatment versus on-treatment was 1.3 days or a 16% reduction (P = 0.04).

Conclusions: The wound angiogenesis assay used in this study was practical, well tolerated, and reproducible. Delays in wound angiogenesis because of BMS-275291 were detectable with this assay. This technique warrants additional investigation in clinical trials of other antiangiogenic agents.

Commentary

Matrix Metalloproteinases, Angiogenesis, and Cancer: Commentary re: A. C. Lockhart et al., Reduction of Wound Angiogenesis in Patients Treated with BMS-275291, a Broad Spectrum Matrix Metalloproteinase Inhibitor. Clin. Cancer Res., 9: 00–00, 2003.

Joyce E. Rundhaug
Clin. Cancer Res. 2003 9: 551-554. [Full Text] [PDF]

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