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

• Published in: Clinical cancer research Vol. 9; no. 2; pp. 586 - 593
• Main Authors: LOCKHART, A. Craig, BRAUN, Rod D, GRICHNIK, James M, PROIA, Alan D, CONWAY, Delina A, HURWITZ, Herbert I, DAOHAI YU, ROSS, Joel R, DEWHIRST, Mark W, HUMPHREY, Jeffrey S, THOMPSON, Seth, WILLIAMS, Kathleen M, KLITZMAN, Bruce, FAN YUAN
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.2003
• Subjects: Antineoplastic agents; Antineoplastic Agents - adverse effects; Biological and medical sciences; Biopsy; Chemotherapy; Humans; Imidazoles; Matrix Metalloproteinase Inhibitors; Medical sciences; Neoplasms - blood supply; Neoplasms - drug therapy; Neoplasms - mortality; Neoplasms - pathology; Neovascularization, Pathologic - prevention & control; Organic Chemicals; Pharmacology. Drug treatments; Survival Analysis; Time Factors; Antineoplastic agent; Human; Solid tumor; Enzyme; Treatment efficiency; Oral administration; Enzyme inhibitor; Metalloendopeptidases; Malignant tumor; Wound; Peptidases; Angiogenesis; Chemotherapy; Treatment; Investigation method; Phase I trial; Hydrolases; Neovascularization; Antiangiogenic agent; Detection
• ISSN: 1078-0432; 1557-3265

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.