This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Galbraith, S. M. Articles by Padhani, A. R. Search for Related Content PubMed PubMed Citation Articles by Galbraith, S. M. Articles by Padhani, A. R. Social Bookmarking                            What's this?

Effects of 5,6-Dimethylxanthenone-4-Acetic Acid on Human Tumor Microcirculation Assessed by Dynamic Contrast-Enhanced Magnetic Resonance Imaging

From the Department of Medical Oncology and Paul Strickland Scanner Centre, Mount Vernon Hospital, Northwood, and Cancer Research Campaign, Drug Development Office, Cambridge Terrace, London, United Kingdom, and Department of Oncology, Waikato Hospital, Hamilton, and Department of Clinical Oncology, Auckland Hospital and Auckland Radiology Group, Auckland, New Zealand.

Address reprint requests to Gordon J.S. Rustin, MD, Department of Oncology, Mount Vernon Hospital, Rickmansworth Rd, Northwood, Middlesex HA6 2RN, United Kingdom; email: rustin{at}mtvern.co.uk

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				J. Landa and L. H. Schwartz Contemporary Imaging in Sarcoma Oncologist, October 1, 2009; 14(10): 1021 - 1038. [Abstract] [Full Text] [PDF]

				G M Tozer, C Kanthou, G Lewis, V E Prise, B Vojnovic, and S A Hill Tumour vascular disrupting agents: combating treatment resistance Br. J. Radiol., October 1, 2008; 81(Special_Issue_1): S12 - S20. [Abstract] [Full Text] [PDF]

				A. Jackson, J. P.B. O'Connor, G. J.M. Parker, and G. C. Jayson Imaging Tumor Vascular Heterogeneity and Angiogenesis using Dynamic Contrast-Enhanced Magnetic Resonance Imaging Clin. Cancer Res., June 15, 2007; 13(12): 3449 - 3459. [Abstract] [Full Text] [PDF]

				A. M. Iga, S. Sarkar, K. M. Sales, M. C. Winslet, and A. M. Seifalian Quantitating Therapeutic Disruption of Tumor Blood Flow with Intravital Video Microscopy Cancer Res., December 15, 2006; 66(24): 11517 - 11519. [Abstract] [Full Text] [PDF]

				P. Workman, E. O. Aboagye, Y.-L. Chung, J. R. Griffiths, R. Hart, M. O. Leach, R. J. Maxwell, P. M. J. McSheehy, P. M. Price, and J. Zweit Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. J Natl Cancer Inst, May 3, 2006; 98(9): 580 - 598. [Abstract] [Full Text] [PDF]

				W. J. van Heeckeren, S. Bhakta, J. Ortiz, J. Duerk, M. M. Cooney, A. Dowlati, K. McCrae, and S. C. Remick Promise of New Vascular-Disrupting Agents Balanced With Cardiac Toxicity: Is It Time for Oncologists to Get to Know Their Cardiologists? J. Clin. Oncol., April 1, 2006; 24(10): 1485 - 1488. [Full Text] [PDF]

				M. J. McKeage, P. Fong, M. Jeffery, B. C. Baguley, P. Kestell, M. Ravic, and M. B. Jameson 5,6-dimethylxanthenone-4-acetic Acid in the treatment of refractory tumors: a phase I safety study of a vascular disrupting agent. Clin. Cancer Res., March 15, 2006; 12(6): 1776 - 1784. [Abstract] [Full Text] [PDF]

				Y. Cao, P. C. Sundgren, C. I. Tsien, T. T. Chenevert, and L. Junck Physiologic and Metabolic Magnetic Resonance Imaging in Gliomas J. Clin. Oncol., March 10, 2006; 24(8): 1228 - 1235. [Abstract] [Full Text] [PDF]

				H. C. Thoeny, F. De Keyzer, V. Vandecaveye, F. Chen, X. Sun, H. Bosmans, R. Hermans, E. K. Verbeken, C. Boesch, G. Marchal, et al. Effect of Vascular Targeting Agent in Rat Tumor Model: Dynamic Contrast-enhanced versus Diffusion-weighted MR Imaging Radiology, November 1, 2005; 237(2): 492 - 499. [Abstract] [Full Text] [PDF]

				G. Liu, H. S. Rugo, G. Wilding, T. M. McShane, J. L. Evelhoch, C. Ng, E. Jackson, F. Kelcz, B. M. Yeh, F. T. Lee Jr, et al. Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study J. Clin. Oncol., August 20, 2005; 23(24): 5464 - 5473. [Abstract] [Full Text] [PDF]

				M. Seshadri, J. A. Spernyak, R. Mazurchuk, S. H. Camacho, A. R. Oseroff, R. T. Cheney, and D. A. Bellnier Tumor Vascular Response to Photodynamic Therapy and the Antivascular Agent 5,6-Dimethylxanthenone-4-Acetic Acid: Implications for Combination Therapy Clin. Cancer Res., June 1, 2005; 11(11): 4241 - 4250. [Abstract] [Full Text] [PDF]

				L. D. McPhail, Y.-L. Chung, B. Madhu, S. Clark, J. R. Griffiths, L. R. Kelland, and S. P. Robinson Tumor Dose Response to the Vascular Disrupting Agent, 5,6-Dimethylxanthenone-4-Acetic Acid, Using In vivo Magnetic Resonance Spectroscopy Clin. Cancer Res., May 15, 2005; 11(10): 3705 - 3713. [Abstract] [Full Text] [PDF]

				J. C. Miller, H. H. Pien, D. Sahani, A. G. Sorensen, and J. H. Thrall Imaging Angiogenesis: Applications and Potential for Drug Development J Natl Cancer Inst, February 2, 2005; 97(3): 172 - 187. [Abstract] [Full Text] [PDF]

				S. Rehman and G. C. Jayson Molecular Imaging of Antiangiogenic Agents Oncologist, February 1, 2005; 10(2): 92 - 103. [Abstract] [Full Text] [PDF]

				S. A. Horner, S. Gould, J. P. Noakes, N. J. Rattray, S. L. Allen, E. Zotova, and J. C. Arezzo Lack of neurotoxicity of the vascular targeting agent ZD6126 following repeated i.v. dosing in the rat Mol. Cancer Ther., July 1, 2004; 3(7): 783 - 791. [Abstract] [Full Text] [PDF]

				J. L. Evelhoch, P. M. LoRusso, Z. He, Z. DelProposto, L. Polin, T. H. Corbett, P. Langmuir, C. Wheeler, A. Stone, J. Leadbetter, et al. Magnetic Resonance Imaging Measurements of the Response of Murine and Human Tumors to the Vascular-Targeting Agent ZD6126 Clin. Cancer Res., June 1, 2004; 10(11): 3650 - 3657. [Abstract] [Full Text] [PDF]

				P. E. Thorpe Vascular Targeting Agents as Cancer Therapeutics Clin. Cancer Res., January 15, 2004; 10(2): 415 - 427. [Abstract] [Full Text] [PDF]

				M. L. Wahl, T. L. Moser, and S. V. Pizzo Angiostatin and Anti-angiogenic Therapy in Human Disease Recent Prog. Horm. Res., January 1, 2004; 59(1): 73 - 104. [Abstract] [Full Text]

				L. Zhao, L.-M. Ching, P. Kestell, and B. C. Baguley Improvement of the Antitumor Activity of Intraperitoneally and Orally Administered 5,6-Dimethylxanthenone-4-Acetic Acid by Optimal Scheduling Clin. Cancer Res., December 15, 2003; 9(17): 6545 - 6550. [Abstract] [Full Text] [PDF]

				G M Tozer Measuring tumour vascular response to antivascular and antiangiogenic drugs Br. J. Radiol., December 1, 2003; 76(suppl_1): S23 - S35. [Abstract] [Full Text] [PDF]

				A R Padhani MRI for assessing antivascular cancer treatments Br. J. Radiol., December 1, 2003; 76(suppl_1): S60 - S80. [Abstract] [Full Text] [PDF]

				S M Galbraith Antivascular cancer treatments: imaging biomarkers in pharmaceutical drug development Br. J. Radiol., December 1, 2003; 76(suppl_1): S83 - S86. [Full Text] [PDF]

				M O Leach, K M Brindle, J L Evelhoch, J R Griffiths, M R Horsman, A Jackson, G Jayson, I R Judson, M V Knopp, R J Maxwell, et al. Assessment of antiangiogenic and antivascular therapeutics using MRI: recommendations for appropriate methodology for clinical trials Br. J. Radiol., December 1, 2003; 76(suppl_1): S87 - S91. [Full Text] [PDF]