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

Albert 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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)586-593
Number of pages8
JournalClinical Cancer Research
Volume9
Issue number2
StatePublished - Feb 1 2003
Externally publishedYes

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Matrix Metalloproteinase Inhibitors
Wounds and Injuries
Blood Vessels
Therapeutics
Biopsy
Angiogenesis Inhibitors
N-((2S)-2-mercapto-1-oxo-4-(3,4,4- trimethyl-2,5-dioxo-1-imidazolidinyl)butyl)-L-leucyl-N,3- dimethyl-L-Valinamide
Research Design
Clinical Trials
Confidence Intervals
Skin

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lockhart, A., Braun, R. D., Yu, D., Ross, J. R., Dewhirst, M. W., Humphrey, J. S., ... Hurwitz, H. I. (2003). Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor. Clinical Cancer Research, 9(2), 586-593.

Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor. / Lockhart, Albert; Braun, Rod D.; Yu, Daohai; Ross, Joel R.; Dewhirst, Mark W.; Humphrey, Jeffrey S.; Thompson, Seth; Williams, Kathleen M.; Klitzman, Bruce; Yuan, Fan; Grichnik, James M; Proia, Alan D.; Conway, Delina A.; Hurwitz, Herbert I.

In: Clinical Cancer Research, Vol. 9, No. 2, 01.02.2003, p. 586-593.

Research output: Contribution to journalArticle

Lockhart, A, Braun, RD, Yu, D, Ross, JR, Dewhirst, MW, Humphrey, JS, Thompson, S, Williams, KM, Klitzman, B, Yuan, F, Grichnik, JM, Proia, AD, Conway, DA & Hurwitz, HI 2003, 'Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor', Clinical Cancer Research, vol. 9, no. 2, pp. 586-593.
Lockhart, Albert ; Braun, Rod D. ; Yu, Daohai ; Ross, Joel R. ; Dewhirst, Mark W. ; Humphrey, Jeffrey S. ; Thompson, Seth ; Williams, Kathleen M. ; Klitzman, Bruce ; Yuan, Fan ; Grichnik, James M ; Proia, Alan D. ; Conway, Delina A. ; Hurwitz, Herbert I. / Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 2. pp. 586-593.
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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.",
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AU - Lockhart, Albert

AU - Braun, Rod D.

AU - Yu, Daohai

AU - Ross, Joel R.

AU - Dewhirst, Mark W.

AU - Humphrey, Jeffrey S.

AU - Thompson, Seth

AU - Williams, Kathleen M.

AU - Klitzman, Bruce

AU - Yuan, Fan

AU - Grichnik, James M

AU - Proia, Alan D.

AU - Conway, Delina A.

AU - Hurwitz, Herbert I.

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Y1 - 2003/2/1

N2 - 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.

AB - 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.

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