Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor.

Abstract

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.

• Authors: A Craig Lockhart, Rod D Braun, Daohai Yu, Joel R Ross, Mark W Dewhirst, Jeffrey S Humphrey, Seth Thompson, Kathleen M Williams, Bruce Klitzman, Fan Yuan, James M Grichnik, Alan D Proia, Delina A Conway, Herbert I Hurwitz
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 9 Issue 2 Pg. 586-93 (Feb 2003) ISSN: 1078-0432 [Print] United States
• PMID: 12576422 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Comment, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Imidazoles
• Matrix Metalloproteinase Inhibitors
• Organic Chemicals
• N-((2S)-2-mercapto-1-oxo-4-(3,4,4- trimethyl-2,5-dioxo-1-imidazolidinyl)butyl)-L-leucyl-N,3- dimethyl-L-Valinamide

Topics

• Antineoplastic Agents (adverse effects)
• Biopsy
• Humans
• Imidazoles
• Matrix Metalloproteinase Inhibitors
• Neoplasms (blood supply, drug therapy, mortality, pathology)
• Neovascularization, Pathologic (prevention & control)
• Organic Chemicals
• Survival Analysis
• Time Factors