Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging

Susan M. Galbraith, Gordon J S Rustin, Martin A. Lodge, N. Jane Taylor, J. James Stirling, Michael Jameson, Paul Thompson, David Hough, Lindsey Gumbrell, Anwar R. Padhani

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

Purpose: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) causes vascular shutdown in preclinical models. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies were performed in the phase I trials to examine changes related to blood flow and permeability in tumor and muscle. Patients and Methods: Sixteen patients treated with DMXAA from 500 to 4,900 mg/m2 had DCE-MRI examinations before and after treatment. The maximum gradient, the maximum enhancement, and the area under the signal-intensity-time curve (AUC) over the first 90 seconds were calculated for each pixel in regions of interest (ROIs) in muscle and tumor, and the median value for each ROI was obtained. Changes after treatment were compared with 95% limits of agreement for an individual and for groups using data from our reproducibility study. Results: Nine of 16 patients had significant reductions in AUC 24 hours after the first dose of DMXAA, and eight of 11 patients had reductions of up to 66% in AUC 24 hours after the last dose. Mean reductions in gradient, enhancement, and AUC were 25%, 18%, and 31%, respectively, 24 hours after the last dose, significantly greater than the 95% limits of change for a group of 11 patients. Enhancement and AUC in muscle 24 hours after the first dose were significantly reduced, but no significant changes were seen 24 hours after the last dose. Conclusion: DMXAA significantly reduces DCE-MRI parameters related to tumor blood flow, over a wide dose range, consistent with the reported tumor vascular targeting activity. Further clinical evaluation of DMXAA is warranted.

Original languageEnglish (US)
Pages (from-to)3826-3840
Number of pages15
JournalJournal of Clinical Oncology
Volume20
Issue number18
DOIs
StatePublished - Sep 15 2002
Externally publishedYes

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vadimezan
Microcirculation
Area Under Curve
Acetic Acid
Magnetic Resonance Imaging
Neoplasms
Muscles
Blood Vessels
Permeability

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Galbraith, S. M., Rustin, G. J. S., Lodge, M. A., Taylor, N. J., Stirling, J. J., Jameson, M., ... Padhani, A. R. (2002). Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging. Journal of Clinical Oncology, 20(18), 3826-3840. https://doi.org/10.1200/JCO.2002.09.144

Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging. / Galbraith, Susan M.; Rustin, Gordon J S; Lodge, Martin A.; Taylor, N. Jane; Stirling, J. James; Jameson, Michael; Thompson, Paul; Hough, David; Gumbrell, Lindsey; Padhani, Anwar R.

In: Journal of Clinical Oncology, Vol. 20, No. 18, 15.09.2002, p. 3826-3840.

Research output: Contribution to journalArticle

Galbraith, SM, Rustin, GJS, Lodge, MA, Taylor, NJ, Stirling, JJ, Jameson, M, Thompson, P, Hough, D, Gumbrell, L & Padhani, AR 2002, 'Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging', Journal of Clinical Oncology, vol. 20, no. 18, pp. 3826-3840. https://doi.org/10.1200/JCO.2002.09.144
Galbraith, Susan M. ; Rustin, Gordon J S ; Lodge, Martin A. ; Taylor, N. Jane ; Stirling, J. James ; Jameson, Michael ; Thompson, Paul ; Hough, David ; Gumbrell, Lindsey ; Padhani, Anwar R. / Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging. In: Journal of Clinical Oncology. 2002 ; Vol. 20, No. 18. pp. 3826-3840.
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abstract = "Purpose: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) causes vascular shutdown in preclinical models. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies were performed in the phase I trials to examine changes related to blood flow and permeability in tumor and muscle. Patients and Methods: Sixteen patients treated with DMXAA from 500 to 4,900 mg/m2 had DCE-MRI examinations before and after treatment. The maximum gradient, the maximum enhancement, and the area under the signal-intensity-time curve (AUC) over the first 90 seconds were calculated for each pixel in regions of interest (ROIs) in muscle and tumor, and the median value for each ROI was obtained. Changes after treatment were compared with 95{\%} limits of agreement for an individual and for groups using data from our reproducibility study. Results: Nine of 16 patients had significant reductions in AUC 24 hours after the first dose of DMXAA, and eight of 11 patients had reductions of up to 66{\%} in AUC 24 hours after the last dose. Mean reductions in gradient, enhancement, and AUC were 25{\%}, 18{\%}, and 31{\%}, respectively, 24 hours after the last dose, significantly greater than the 95{\%} limits of change for a group of 11 patients. Enhancement and AUC in muscle 24 hours after the first dose were significantly reduced, but no significant changes were seen 24 hours after the last dose. Conclusion: DMXAA significantly reduces DCE-MRI parameters related to tumor blood flow, over a wide dose range, consistent with the reported tumor vascular targeting activity. Further clinical evaluation of DMXAA is warranted.",
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AU - Galbraith, Susan M.

AU - Rustin, Gordon J S

AU - Lodge, Martin A.

AU - Taylor, N. Jane

AU - Stirling, J. James

AU - Jameson, Michael

AU - Thompson, Paul

AU - Hough, David

AU - Gumbrell, Lindsey

AU - Padhani, Anwar R.

PY - 2002/9/15

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N2 - Purpose: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) causes vascular shutdown in preclinical models. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies were performed in the phase I trials to examine changes related to blood flow and permeability in tumor and muscle. Patients and Methods: Sixteen patients treated with DMXAA from 500 to 4,900 mg/m2 had DCE-MRI examinations before and after treatment. The maximum gradient, the maximum enhancement, and the area under the signal-intensity-time curve (AUC) over the first 90 seconds were calculated for each pixel in regions of interest (ROIs) in muscle and tumor, and the median value for each ROI was obtained. Changes after treatment were compared with 95% limits of agreement for an individual and for groups using data from our reproducibility study. Results: Nine of 16 patients had significant reductions in AUC 24 hours after the first dose of DMXAA, and eight of 11 patients had reductions of up to 66% in AUC 24 hours after the last dose. Mean reductions in gradient, enhancement, and AUC were 25%, 18%, and 31%, respectively, 24 hours after the last dose, significantly greater than the 95% limits of change for a group of 11 patients. Enhancement and AUC in muscle 24 hours after the first dose were significantly reduced, but no significant changes were seen 24 hours after the last dose. Conclusion: DMXAA significantly reduces DCE-MRI parameters related to tumor blood flow, over a wide dose range, consistent with the reported tumor vascular targeting activity. Further clinical evaluation of DMXAA is warranted.

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