title: Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: A Craig
authors.initials: AC
authors.lastname: Lockhart
authors.forename: Rod D
authors.initials: RD
authors.lastname: Braun
authors.forename: Daohai
authors.initials: D
authors.lastname: Yu
authors.forename: Joel R
authors.initials: JR
authors.lastname: Ross
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Humphrey
authors.forename: Seth
authors.initials: S
authors.lastname: Thompson
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Williams
authors.forename: Bruce
authors.initials: B
authors.lastname: Klitzman
authors.forename: Fan
authors.initials: F
authors.lastname: Yuan
authors.forename: James M
authors.initials: JM
authors.lastname: Grichnik
authors.forename: Alan D
authors.initials: AD
authors.lastname: Proia
authors.forename: Delina A
authors.initials: DA
authors.lastname: Conway
authors.forename: Herbert I
authors.initials: HI
authors.lastname: Hurwitz
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D001706:Biopsy; D006801:Humans; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009930:Organic Chemicals; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D009930:Organic Chemicals; C422302:N-((2S)-2-mercapto-1-oxo-4-(3,4,4- trimethyl-2,5-dioxo-1-imidazolidinyl)butyl)-L-leucyl-N,3- dimethyl-L-Valinamide