Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor.
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.
Lockhart
A Craig
AC
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Braun
Rod D
RD
Yu
Daohai
D
Ross
Joel R
JR
Dewhirst
Mark W
MW
Humphrey
Jeffrey S
JS
Thompson
Seth
S
Williams
Kathleen M
KM
Klitzman
Bruce
B
Yuan
Fan
F
Grichnik
James M
JM
Proia
Alan D
AD
Conway
Delina A
DA
Hurwitz
Herbert I
HI
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
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