Originally published as JCO Early Release 10.1200/JCO.2003.05.187 on June 13 2003

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 Rustin, G. J.S. Search for Related Content PubMed PubMed Citation Articles by Galbraith, S. M. Articles by Rustin, G. J.S. Social Bookmarking                            What's this?

Combretastatin A4 Phosphate Has Tumor Antivascular Activity in Rat and Man as Demonstrated by Dynamic Magnetic Resonance Imaging

Susan M. Galbraith, Ross J. Maxwell, Martin A. Lodge, Gillian M. Tozer, John Wilson, N. Jane Taylor, J. James Stirling, Luiza Sena, Anwar R. Padhani, Gordon J.S. Rustin

From the Gray Cancer Institute, Paul Strickland Scanner Centre, Department of Medical Oncology, Mount Vernon Hospital, Northwood, Middlesex; and Cancer Research United Kingdom, Cambridge Terrace, London, United Kingdom.

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

Purpose: Combretastatin A4 phosphate (CA4P) is a novel vascular targeting agent. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) studies were performed to examine changes in parameters related to blood flow and vascular permeability in tumor and normal tissue after CA4P treatment.

Materials and Methods: Changes in kinetic DCE-MRI parameters (transfer constant [K^trans] and area under contrast medium-time curve [AUC]) over 24 hours after treatment with CA4P were measured in 18 patients in a phase I trial and compared with those obtained in the rat P22 carcinosarcoma model, using the same imaging technique. Rats were treated with 30 mg/kg of CA4P; patients received escalating doses from 5 to 114 mg/m².

Results: A similar pattern and time course of change in tumor and normal tissue parameters was seen in rats and humans. Rat tumor K^trans was reduced by 64% 6 hours after treatment with CA4P (30 mg/kg). No significant reductions in kidney or muscle parameters were seen. Significant reductions were seen in tumor K^trans in six of 16 patients treated at 52 mg/m², with a significant group mean reduction of 37% and 29% at 4 and 24 hours, respectively, after treatment. The mean reduction in tumor initial area under the gadolinium–diethylenetriamine pentaacetic acid concentration-time curve (AUC) was 33% and 18%, respectively, at these times. No reduction was seen in muscle K^trans or in kidney AUC in group analysis of the clinical data.

Conclusion: CA4P acutely reduces K^trans in human as well as rat tumors at well-tolerated doses, with no significant changes in kidney or muscle, providing proof of principle that this drug has tumor antivascular activity in rats and humans.

Supported by grants from the Community Fund and Cancer Research United Kingdom. CA4P was supplied by OXiGENE, Inc, Watertown, MA.

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

This article has been cited by other articles:

				J. P.B. O'Connor, R. A.D. Carano, A. R. Clamp, J. Ross, C. C.K. Ho, A. Jackson, G. J.M. Parker, C. J. Rose, F. V. Peale, M. Friesenhahn, et al. Quantifying Antivascular Effects of Monoclonal Antibodies to Vascular Endothelial Growth Factor: Insights from Imaging Clin. Cancer Res., November 1, 2009; 15(21): 6674 - 6682. [Abstract] [Full Text] [PDF]

				T. Meyer, A. M. Gaya, G. Dancey, M. R.L. Stratford, S. Othman, S. K. Sharma, D. Wellsted, N. J. Taylor, J. J. Stirling, L. Poupard, et al. A Phase I Trial of Radioimmunotherapy with 131I-A5B7 Anti-CEA Antibody in Combination with Combretastatin-A4-Phosphate in Advanced Gastrointestinal Carcinomas Clin. Cancer Res., July 1, 2009; 15(13): 4484 - 4492. [Abstract] [Full Text] [PDF]

				G. M. Tozer, V. E. Prise, G. Lewis, S. Xie, I. Wilson, and S. A. Hill Nitric Oxide Synthase Inhibition Enhances the Tumor Vascular-Damaging Effects of Combretastatin A-4 3-O-Phosphate at Clinically Relevant Doses Clin. Cancer Res., June 1, 2009; 15(11): 3781 - 3790. [Abstract] [Full Text] [PDF]

				E. L. Schwartz Antivascular Actions of Microtubule-Binding Drugs Clin. Cancer Res., April 15, 2009; 15(8): 2594 - 2601. [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]

				D. Zhao, E. Richer, P. P. Antich, and R. P. Mason Antivascular effects of combretastatin A4 phosphate in breast cancer xenograft assessed using dynamic bioluminescence imaging and confirmed by MRI FASEB J, July 1, 2008; 22(7): 2445 - 2451. [Abstract] [Full Text] [PDF]

				G. M. Tozer, S. Akerman, N. A. Cross, P. R. Barber, M. A. Bjorndahl, O. Greco, S. Harris, S. A. Hill, D. J. Honess, C. R. Ireson, et al. Blood Vessel Maturation and Response to Vascular-Disrupting Therapy in Single Vascular Endothelial Growth Factor-A Isoform-Producing Tumors Cancer Res., April 1, 2008; 68(7): 2301 - 2311. [Abstract] [Full Text] [PDF]

				T. J. Kim, M. Ravoori, C. N. Landen, A. A. Kamat, L. Y. Han, C. Lu, Y. G. Lin, W. M. Merritt, N. Jennings, W. A. Spannuth, et al. Antitumor and Antivascular Effects of AVE8062 in Ovarian Carcinoma Cancer Res., October 1, 2007; 67(19): 9337 - 9345. [Abstract] [Full Text] [PDF]

				S.-C. J. Yeung, M. She, H. Yang, J. Pan, L. Sun, and D. Chaplin Combination Chemotherapy Including Combretastatin A4 Phosphate and Paclitaxel Is Effective against Anaplastic Thyroid Cancer in a Nude Mouse Xenograft Model J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2902 - 2909. [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]

				V. Goh, S. Halligan, and C. I. Bartram Quantitative Tumor Perfusion Assessment with Multidetector CT: Are Measurements from Two Commercial Software Packages Interchangeable? Radiology, March 1, 2007; 242(3): 777 - 782. [Abstract] [Full Text] [PDF]

				M. A. Rosen and M. D. Schnall Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Assessing Tumor Vascularity and Vascular Effects of Targeted Therapies in Renal Cell Carcinoma Clin. Cancer Res., January 15, 2007; 13(2): 770s - 776s. [Abstract] [Full Text] [PDF]

				M. R. Horsman and D. W. Siemann Pathophysiologic Effects of Vascular-Targeting Agents and the Implications for Combination with Conventional Therapies Cancer Res., December 15, 2006; 66(24): 11520 - 11539. [Abstract] [Full Text] [PDF]

				R. Ansiaux, C. Baudelet, B. F. Jordan, N. Crokart, P. Martinive, J. DeWever, V. Gregoire, O. Feron, and B. Gallez Mechanism of Reoxygenation after Antiangiogenic Therapy Using SU5416 and Its Importance for Guiding Combined Antitumor Therapy Cancer Res., October 1, 2006; 66(19): 9698 - 9704. [Abstract] [Full Text] [PDF]

				Q. S. Ng, V. Goh, E. Klotz, H. Fichte, M. I. Saunders, P. J. Hoskin, and A. R. Padhani Quantitative Assessment of Lung Cancer Perfusion Using MDCT: Does Measurement Reproducibility Improve with Greater Tumor Volume Coverage? Am. J. Roentgenol., October 1, 2006; 187(4): 1079 - 1084. [Abstract] [Full Text] [PDF]

				W. Badn, S. Kalliomaki, B. Widegren, and H. O. Sjogren Low-Dose Combretastatin A4 Phosphate Enhances the Immune Response of Tumor Hosts to Experimental Colon Carcinoma Clin. Cancer Res., August 1, 2006; 12(15): 4714 - 4719. [Abstract] [Full Text] [PDF]

				V Goh, S Halligan, L Gartner, P Bassett, and C I Bartram Quantitative colorectal cancer perfusion measurement by multidetector-row CT: does greater tumour coverage improve measurement reproducibility? Br. J. Radiol., July 1, 2006; 79(943): 578 - 583. [Abstract] [Full Text] [PDF]

				H. W. Salmon and D. W. Siemann Effect of the Second-Generation Vascular Disrupting Agent OXi4503 on Tumor Vascularity. Clin. Cancer Res., July 1, 2006; 12(13): 4090 - 4094. [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]

				Q.-S. Ng, V. Goh, H. Fichte, E. Klotz, P. Fernie, M. I. Saunders, P. J. Hoskin, and A. R. Padhani Lung Cancer Perfusion at Multi-Detector Row CT: Reproducibility of Whole Tumor Quantitative Measurements Radiology, May 1, 2006; 239(2): 547 - 553. [Abstract] [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]

				J. A. d'Arcy, D. J. Collins, A. R. Padhani, S. Walker-Samuel, J. Suckling, and M. O. Leach Informatics in Radiology (infoRAD): Magnetic Resonance Imaging Workbench: Analysis and Visualization of Dynamic Contrast-enhanced MR Imaging Data. RadioGraphics, March 1, 2006; 26(2): 621 - 632. [Abstract] [Full Text] [PDF]

				R. Ansiaux, C. Baudelet, G. O. Cron, J. Segers, C. Dessy, P. Martinive, J. De Wever, J. Verrax, V. Wauthier, N. Beghein, et al. Botulinum Toxin Potentiates Cancer Radiotherapy and Chemotherapy Clin. Cancer Res., February 15, 2006; 12(4): 1276 - 1283. [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]

				M. van Vliet, C. F. van Dijke, P. A. Wielopolski, T. L. M. ten Hagen, J. F. Veenland, A. Preda, A. J. Loeve, A. M. M. Eggermont, and G. P. Krestin MR Angiography of Tumor-related Vasculature: From the Clinic to the Micro-environment RadioGraphics, October 1, 2005; 25(suppl_1): S85 - S97. [Abstract] [Full Text] [PDF]

				A S K Dzik-Jurasz Pelvic malignancy: integrating form and function Br. J. Radiol., October 1, 2005; 78(Special_Issue_2): S86 - S93. [Abstract] [Full Text] [PDF]

				J. Evelhoch, M. Garwood, D. Vigneron, M. Knopp, D. Sullivan, A. Menkens, L. Clarke, and G. Liu Expanding the Use of Magnetic Resonance in the Assessment of Tumor Response to Therapy: Workshop Report Cancer Res., August 15, 2005; 65(16): 7041 - 7044. [Abstract] [Full Text] [PDF]

				H. C. Thoeny, F. De Keyzer, F. Chen, Y. Ni, W. Landuyt, E. K. Verbeken, H. Bosmans, G. Marchal, and R. Hermans Diffusion-weighted MR Imaging in Monitoring the Effect of a Vascular Targeting Agent on Rhabdomyosarcoma in Rats Radiology, March 1, 2005; 234(3): 756 - 764. [Abstract] [Full Text] [PDF]

				G. Gasparini, R. Longo, M. Fanelli, and B. A. Teicher Combination of Antiangiogenic Therapy With Other Anticancer Therapies: Results, Challenges, and Open Questions J. Clin. Oncol., February 20, 2005; 23(6): 1295 - 1311. [Abstract] [Full Text] [PDF]

				J. H. Bilenker, K. T. Flaherty, M. Rosen, L. Davis, M. Gallagher, J. P. Stevenson, W. Sun, D. Vaughn, B. Giantonio, R. Zimmer, et al. Phase I Trial of Combretastatin A-4 Phosphate with Carboplatin Clin. Cancer Res., February 15, 2005; 11(4): 1527 - 1533. [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]

				C. Kanthou, O. Greco, A. Stratford, I. Cook, R. Knight, O. Benzakour, and G. Tozer The Tubulin-Binding Agent Combretastatin A-4-Phosphate Arrests Endothelial Cells in Mitosis and Induces Mitotic Cell Death Am. J. Pathol., October 1, 2004; 165(4): 1401 - 1411. [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]

				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]

				A S K Dzik-Jurasz Molecular imaging in vivo: an introduction Br. J. Radiol., December 1, 2003; 76(suppl_2): S98 - S109. [Full Text] [PDF]

				J. M. Collins Functional Imaging in Phase I Studies: Decorations or Decision Making? J. Clin. Oncol., August 1, 2003; 21(15): 2807 - 2809. [Full Text] [PDF]

				G. J.S. Rustin, S. M. Galbraith, H. Anderson, M. Stratford, L. K. Folkes, L. Sena, L. Gumbrell, and P. M. Price Phase I Clinical Trial of Weekly Combretastatin A4 Phosphate: Clinical and Pharmacokinetic Results J. Clin. Oncol., August 1, 2003; 21(15): 2815 - 2822. [Abstract] [Full Text] [PDF]