Abstract

Vascular targeting agents on their own have been shown to be insufficient for complete treatment of solid tumors, emphasizing the importance of studying the vascular effects of these drugs for their use with conventional therapies in the clinic. First-pass fluorescence imaging combined with hyperspectral imaging of hemoglobin saturation of microvessels in the murine dorsal window chamber model provides an easily implementable, low cost method to analyze tumor vascular response to these agents in real-time. In this study, the authors utilized these methods to spectroscopically demonstrate distinct vessel structure, blood flow and oxygenation changes in human Caki-2 renal cell carcinoma following treatment with OXi4503 alone, Sunitinib alone and both drugs together. We showed that treatment with OXi4503 plus Sunitinib destroyed existing tumor microvessels, inhibited blood vessel recovery and impaired Caki-2 tumor growth significantly more than either treatment alone.

© 2014 Optical Society of America

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2013 (2)

A. N. Fontanella, T. Schroeder, D. W. Hochman, R. E. Chen, G. Hanna, M. M. Haglund, T. W. Secomb, G. M. Palmer, and M. W. Dewhirst, “Quantitative mapping of hemodynamics in the lung, brain, and dorsal window chamber-grown tumors using a novel, automated algorithm,” Microcirculation20(8), 724–735 (2013).
[PubMed]

J. A. Lee, R. T. Kozikowski, and B. S. Sorg, “Combination of spectral and fluorescence imaging microscopy for wide-field in vivo analysis of microvessel blood supply and oxygenation,” Opt. Lett.38(3), 332–334 (2013).
[CrossRef] [PubMed]

2012 (7)

V. Moreno Garcia, B. Basu, L. R. Molife, and S. B. Kaye, “Combining antiangiogenics to overcome resistance: rationale and clinical experience,” Clin. Cancer Res.18(14), 3750–3761 (2012).
[CrossRef] [PubMed]

P. Nathan, M. Zweifel, A. R. Padhani, D. M. Koh, M. Ng, D. J. Collins, A. Harris, C. Carden, J. Smythe, N. Fisher, N. J. Taylor, J. J. Stirling, S. P. Lu, M. O. Leach, G. J. S. Rustin, and I. Judson, “Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer,” Clin. Cancer Res.18(12), 3428–3439 (2012).
[CrossRef] [PubMed]

B. J. Vakoc, D. Fukumura, R. K. Jain, and B. E. Bouma, “Cancer imaging by optical coherence tomography: preclinical progress and clinical potential,” Nat. Rev. Cancer12(5), 363–368 (2012).
[CrossRef] [PubMed]

M. Taylor, F. Billiot, V. Marty, V. Rouffiac, P. Cohen, E. Tournay, P. Opolon, F. Louache, G. Vassal, C. Laplace-Builhé, P. Vielh, J. C. Soria, and F. Farace, “Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells,” Cancer Discov.2(5), 434–449 (2012).
[CrossRef] [PubMed]

L. Nguyen, T. Fifis, C. Malcontenti-Wilson, L. S. Chan, P. N. Costa, M. Nikfarjam, V. Muralidharan, and C. Christophi, “Spatial morphological and molecular differences within solid tumors may contribute to the failure of vascular disruptive agent treatments,” BMC Cancer12(1), 522 (2012).
[CrossRef] [PubMed]

J. V. Gaustad, T. G. Simonsen, M. N. Leinaas, and E. K. Rofstad, “Sunitinib treatment does not improve blood supply but induces hypoxia in human melanoma xenografts,” BMC Cancer12(1), 388 (2012).
[CrossRef] [PubMed]

T. Nielsen, T. Wittenborn, and M. R. Horsman, “Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in preclinical studies of antivascular treatments,” Pharmaceutics4(4), 563–589 (2012).
[CrossRef] [PubMed]

2011 (8)

D. W. Siemann, “The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents,” Cancer Treat. Rev.37(1), 63–74 (2011).
[CrossRef] [PubMed]

B. A. Teicher, “Antiangiogenic agents and targets: a perspective,” Biochem. Pharmacol.81(1), 6–12 (2011).
[CrossRef] [PubMed]

P. Carmeliet and R. K. Jain, “Molecular mechanisms and clinical applications of angiogenesis,” Nature473(7347), 298–307 (2011).
[CrossRef] [PubMed]

G. M. Palmer, A. N. Fontanella, S. Shan, G. Hanna, G. Zhang, C. L. Fraser, and M. W. Dewhirst, “In vivo optical molecular imaging and analysis in mice using dorsal window chamber models applied to hypoxia, vasculature and fluorescent reporters,” Nat. Protoc.6(9), 1355–1366 (2011).
[CrossRef] [PubMed]

R. T. Ullrich, J. F. Jikeli, M. Diedenhofen, P. Böhm-Sturm, M. Unruh, S. Vollmar, and M. Hoehn, “In-vivo visualization of tumor microvessel density and response to anti-angiogenic treatment by high resolution MRI in mice,” PLoS ONE6(5), e19592 (2011).
[CrossRef] [PubMed]

A. J. Moy, S. M. White, E. S. Indrawan, J. Lotfi, M. J. Nudelman, S. J. Costantini, N. Agarwal, W. Jia, K. M. Kelly, B. S. Sorg, and B. Choi, “Wide-field functional imaging of blood flow and hemoglobin oxygen saturation in the rodent dorsal window chamber,” Microvasc. Res.82(3), 199–209 (2011).
[CrossRef] [PubMed]

M. J. Machado and C. A. Mitchell, “Temporal changes in microvessel leakiness during wound healing discriminated by in vivo fluorescence recovery after photobleaching,” J. Physiol.589(19), 4681–4696 (2011).
[CrossRef] [PubMed]

S. Matsumoto, S. Batra, K. Saito, H. Yasui, R. Choudhuri, C. Gadisetti, S. Subramanian, N. Devasahayam, J. P. Munasinghe, J. B. Mitchell, and M. C. Krishna, “Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia,” Cancer Res.71(20), 6350–6359 (2011).
[CrossRef] [PubMed]

2010 (4)

M. Wankhede, C. Dedeugd, D. W. Siemann, and B. S. Sorg, “In vivo functional differences in microvascular response of 4T1 and Caki-1 tumors after treatment with OXi4503,” Oncol. Rep.23(3), 685–692 (2010).
[PubMed]

S. Dufort, L. Sancey, C. Wenk, V. Josserand, and J. L. Coll, “Optical small animal imaging in the drug discovery process,” Biochim. Biophys. Acta1798(12), 2266–2273 (2010).
[CrossRef] [PubMed]

G. J. Madlambayan, A. M. Meacham, K. Hosaka, S. Mir, M. Jorgensen, E. W. Scott, D. W. Siemann, and C. R. Cogle, “Leukemia regression by vascular disruption and antiangiogenic therapy,” Blood116(9), 1539–1547 (2010).
[CrossRef] [PubMed]

J. H. Tai, J. Tessier, A. J. Ryan, L. Hoffman, X. Chen, and T. Y. Lee, “Assessment of acute antivascular effects of vandetanib with high-resolution dynamic contrast-enhanced computed tomographic imaging in a human colon tumor xenograft model in the nude rat,” Neoplasia12(9), 697–707 (2010).
[PubMed]

2009 (5)

J. A. Nagy, S. H. Chang, A. M. Dvorak, and H. F. Dvorak, “Why are tumour blood vessels abnormal and why is it important to know?” Br. J. Cancer100(6), 865–869 (2009).
[CrossRef] [PubMed]

M. Czabanka, M. Vinci, F. Heppner, A. Ullrich, and P. Vajkoczy, “Effects of sunitinib on tumor hemodynamics and delivery of chemotherapy,” Int. J. Cancer124(6), 1293–1300 (2009).
[CrossRef] [PubMed]

G. G. Hillman, V. Singh-Gupta, H. Zhang, A. K. Al-Bashir, Y. Katkuri, M. Li, C. K. Yunker, A. D. Patel, J. Abrams, and E. M. Haacke, “Dynamic Contrast-Enhanced Magnetic Resonance Imaging of Vascular Changes Induced by Sunitinib in Papillary Renal Cell Carcinoma Xenograft Tumors,” Neoplasia11(9), 910–920 (2009).
[PubMed]

M. C. Skala, A. Fontanella, H. Hendargo, M. W. Dewhirst, and J. A. Izatt, “Combined hyperspectral and spectral domain optical coherence tomography microscope for noninvasive hemodynamic imaging,” Opt. Lett.34(3), 289–291 (2009).
[CrossRef] [PubMed]

C. deDeugd, M. Wankhede, and B. S. Sorg, “Multimodal optical imaging of microvessel network convective oxygen transport dynamics,” Appl. Opt.48(10), D187–D197 (2009).
[CrossRef] [PubMed]

2008 (7)

P. B. Jones, H. K. Shin, D. A. Boas, B. T. Hyman, M. A. Moskowitz, C. Ayata, and A. K. Dunn, “Simultaneous multispectral reflectance imaging and laser speckle flowmetry of cerebral blood flow and oxygen metabolism in focal cerebral ischemia,” J. Biomed. Opt.13(4), 044007 (2008).
[CrossRef] [PubMed]

G. M. Tozer, S. Akerman, N. A. Cross, P. R. Barber, M. A. Björndahl, O. Greco, S. Harris, S. A. Hill, D. J. Honess, C. R. Ireson, K. L. Pettyjohn, V. E. Prise, C. C. Reyes-Aldasoro, C. Ruhrberg, D. T. Shima, and C. Kanthou, “Blood vessel maturation and response to vascular-disrupting therapy in single vascular endothelial growth factor-A isoform-producing tumors,” Cancer Res.68(7), 2301–2311 (2008).
[CrossRef] [PubMed]

K. S. Øye, G. Gulati, B. A. Graff, J. V. Gaustad, K. G. Brurberg, and E. K. Rofstad, “A novel method for mapping the heterogeneity in blood supply to normal and malignant tissues in the mouse dorsal window chamber,” Microvasc. Res.75(2), 179–187 (2008).
[CrossRef] [PubMed]

C. Malcontenti-Wilson, L. Chan, M. Nikfarjam, V. Muralidharan, and C. Christophi, “Vascular targeting agent Oxi4503 inhibits tumor growth in a colorectal liver metastases model,” J. Gastroenterol. Hepatol.23(7 Pt 2), e96–e104 (2008).
[CrossRef] [PubMed]

J. V. Gaustad, K. G. Brurberg, T. G. Simonsen, C. S. Mollatt, and E. K. Rofstad, “Tumor vascularity assessed by magnetic resonance imaging and intravital microscopy imaging,” Neoplasia10(4), 354–362 (2008).
[PubMed]

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2007 (1)

J. G. Christensen, “A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities,” Ann. Oncol.18(Suppl 10), x3–x10 (2007).
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2006 (3)

M. R. Horsman and D. W. Siemann, “Pathophysiologic effects of vascular-targeting agents and the implications for combination with conventional therapies,” Cancer Res.66(24), 11520–11539 (2006).
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H. W. Salmon and D. W. Siemann, “Effect of the second-generation vascular disrupting agent OXi4503 on tumor vascularity,” Clin. Cancer Res.12(13), 4090–4094 (2006).
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M. R. Dreher, W. G. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti, “Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers,” J. Natl. Cancer Inst.98(5), 335–344 (2006).
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2005 (6)

B. S. Sorg, B. J. Moeller, O. Donovan, Y. T. Cao, and M. W. Dewhirst, “Hyperspectral imaging of hemoglobin saturation in tumor microvasculature and tumor hypoxia development,” J. Biomed. Opt.10(4), 044004 (2005).
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D. W. Siemann and W. Shi, “Dual-agent targeting of the tumor vasculature: combining avastin with CA4P or OXi4503,” Clin. Cancer Res.11, 8968S (2005).

A. D. Yang, T. W. Bauer, E. R. Camp, R. Somcio, W. B. Liu, F. Fan, and L. M. Ellis, “Improving delivery of antineoplastic agents with anti-vascular endothelial growth factor therapy,” Cancer103(8), 1561–1570 (2005).
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R. K. Jain, “Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy,” Science307(5706), 58–62 (2005).
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W. Y. Shi and D. W. Siemann, “Targeting the tumor vasculature: Enhancing antitumor efficacy through combination treatment with ZD6126 and ZD6474,” In Vivo19(6), 1045–1050 (2005).
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D. W. Siemann, M. C. Bibby, G. G. Dark, A. P. Dicker, F. A. L. M. Eskens, M. R. Horsman, D. Marmé, and P. M. Lorusso, “Differentiation and definition of vascular-targeted therapies,” Clin. Cancer Res.11(2 Pt 1), 416–420 (2005).
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2004 (5)

P. E. Thorpe, “Vascular targeting agents as cancer therapeutics,” Clin. Cancer Res.10(2), 415–427 (2004).
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Y. Z. Sheng, J. Y. Hua, K. G. Pinney, C. M. Garner, R. R. Kane, J. A. Prezioso, D. J. Chaplin, and K. Edvardsen, “Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis,” Int. J. Cancer111(4), 604–610 (2004).
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D. W. Siemann and W. Y. Shi, “Efficacy of combined antiangiogenic and vascular disrupting agents in treatment of solid tumors,” Int. J. Radiat. Oncol. Biol. Phys.60(4), 1233–1240 (2004).
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2003 (4)

D. M. McDonald and P. L. Choyke, “Imaging of angiogenesis: from microscope to clinic,” Nat. Med.9(6), 713–725 (2003).
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J. Y. Hua, Y. Z. Sheng, K. G. Pinney, C. M. Garner, R. R. Kane, J. A. Prezioso, G. R. Pettit, D. J. Chaplin, and K. Edvardsen, “Oxi4503, a novel vascular targeting agent: Effects on blood flow and antitumor activity in comparison to combretastatin A-4 phosphate,” Anticancer Res.23(2B), 1433–1440 (2003).
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H. L. Anderson, J. T. Yap, M. P. Miller, A. Robbins, T. Jones, and P. M. Price, “Assessment of pharmacodynamic vascular response in a phase I trial of combretastatin A4 phosphate,” J. Clin. Oncol.21(15), 2823–2830 (2003).
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K. G. Brurberg, B. A. Graff, and E. K. Rofstad, “Temporal heterogeneity in oxygen tension in human melanoma xenografts,” Br. J. Cancer89(2), 350–356 (2003).
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2001 (1)

G. M. Tozer, V. E. Prise, J. Wilson, M. Cemazar, S. Shan, M. W. Dewhirst, P. R. Barber, B. Vojnovic, and D. J. Chaplin, “Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate: intravital microscopy and measurement of vascular permeability,” Cancer Res.61(17), 6413–6422 (2001).
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1997 (1)

R. D. Shonat, E. S. Wachman, W. H. Niu, A. P. Koretsky, and D. L. Farkas, “Near-simultaneous hemoglobin saturation and oxygen tension maps in mouse brain using an AOTF microscope,” Biophys. J.73(3), 1223–1231 (1997).
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1995 (2)

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1971 (1)

J. Folkman, “Tumor angiogenesis: therapeutic Implications,” N. Engl. J. Med.285(21), 1182–1186 (1971).
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1965 (1)

A. D. Bangham, M. M. Standish, and J. C. Watkins, “Diffusion of Univalent Ions Across the Lamellae of Swollen Phospholipids,” J. Mol. Biol.13(1), 238–252 (1965).
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Abrams, J.

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G. G. Hillman, V. Singh-Gupta, H. Zhang, A. K. Al-Bashir, Y. Katkuri, M. Li, C. K. Yunker, A. D. Patel, J. Abrams, and E. M. Haacke, “Dynamic Contrast-Enhanced Magnetic Resonance Imaging of Vascular Changes Induced by Sunitinib in Papillary Renal Cell Carcinoma Xenograft Tumors,” Neoplasia11(9), 910–920 (2009).
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Anderson, H. L.

H. L. Anderson, J. T. Yap, M. P. Miller, A. Robbins, T. Jones, and P. M. Price, “Assessment of pharmacodynamic vascular response in a phase I trial of combretastatin A4 phosphate,” J. Clin. Oncol.21(15), 2823–2830 (2003).
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Ayata, C.

P. B. Jones, H. K. Shin, D. A. Boas, B. T. Hyman, M. A. Moskowitz, C. Ayata, and A. K. Dunn, “Simultaneous multispectral reflectance imaging and laser speckle flowmetry of cerebral blood flow and oxygen metabolism in focal cerebral ischemia,” J. Biomed. Opt.13(4), 044007 (2008).
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Bangham, A. D.

A. D. Bangham, M. M. Standish, and J. C. Watkins, “Diffusion of Univalent Ions Across the Lamellae of Swollen Phospholipids,” J. Mol. Biol.13(1), 238–252 (1965).
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Barber, P. R.

G. M. Tozer, S. Akerman, N. A. Cross, P. R. Barber, M. A. Björndahl, O. Greco, S. Harris, S. A. Hill, D. J. Honess, C. R. Ireson, K. L. Pettyjohn, V. E. Prise, C. C. Reyes-Aldasoro, C. Ruhrberg, D. T. Shima, and C. Kanthou, “Blood vessel maturation and response to vascular-disrupting therapy in single vascular endothelial growth factor-A isoform-producing tumors,” Cancer Res.68(7), 2301–2311 (2008).
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G. M. Tozer, V. E. Prise, J. Wilson, M. Cemazar, S. Shan, M. W. Dewhirst, P. R. Barber, B. Vojnovic, and D. J. Chaplin, “Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate: intravital microscopy and measurement of vascular permeability,” Cancer Res.61(17), 6413–6422 (2001).
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A. D. Yang, T. W. Bauer, E. R. Camp, R. Somcio, W. B. Liu, F. Fan, and L. M. Ellis, “Improving delivery of antineoplastic agents with anti-vascular endothelial growth factor therapy,” Cancer103(8), 1561–1570 (2005).
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D. W. Siemann, M. C. Bibby, G. G. Dark, A. P. Dicker, F. A. L. M. Eskens, M. R. Horsman, D. Marmé, and P. M. Lorusso, “Differentiation and definition of vascular-targeted therapies,” Clin. Cancer Res.11(2 Pt 1), 416–420 (2005).
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G. M. Tozer, S. Akerman, N. A. Cross, P. R. Barber, M. A. Björndahl, O. Greco, S. Harris, S. A. Hill, D. J. Honess, C. R. Ireson, K. L. Pettyjohn, V. E. Prise, C. C. Reyes-Aldasoro, C. Ruhrberg, D. T. Shima, and C. Kanthou, “Blood vessel maturation and response to vascular-disrupting therapy in single vascular endothelial growth factor-A isoform-producing tumors,” Cancer Res.68(7), 2301–2311 (2008).
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F. Winkler, S. V. Kozin, R. T. Tong, S. S. Chae, M. F. Booth, I. Garkavtsev, L. Xu, D. J. Hicklin, D. Fukumura, E. di Tomaso, L. L. Munn, and R. K. Jain, “Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases,” Cancer Cell6(6), 553–563 (2004).
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K. S. Øye, G. Gulati, B. A. Graff, J. V. Gaustad, K. G. Brurberg, and E. K. Rofstad, “A novel method for mapping the heterogeneity in blood supply to normal and malignant tissues in the mouse dorsal window chamber,” Microvasc. Res.75(2), 179–187 (2008).
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J. V. Gaustad, K. G. Brurberg, T. G. Simonsen, C. S. Mollatt, and E. K. Rofstad, “Tumor vascularity assessed by magnetic resonance imaging and intravital microscopy imaging,” Neoplasia10(4), 354–362 (2008).
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A. D. Yang, T. W. Bauer, E. R. Camp, R. Somcio, W. B. Liu, F. Fan, and L. M. Ellis, “Improving delivery of antineoplastic agents with anti-vascular endothelial growth factor therapy,” Cancer103(8), 1561–1570 (2005).
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B. S. Sorg, B. J. Moeller, O. Donovan, Y. T. Cao, and M. W. Dewhirst, “Hyperspectral imaging of hemoglobin saturation in tumor microvasculature and tumor hypoxia development,” J. Biomed. Opt.10(4), 044004 (2005).
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P. Nathan, M. Zweifel, A. R. Padhani, D. M. Koh, M. Ng, D. J. Collins, A. Harris, C. Carden, J. Smythe, N. Fisher, N. J. Taylor, J. J. Stirling, S. P. Lu, M. O. Leach, G. J. S. Rustin, and I. Judson, “Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer,” Clin. Cancer Res.18(12), 3428–3439 (2012).
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G. M. Tozer, V. E. Prise, J. Wilson, M. Cemazar, S. Shan, M. W. Dewhirst, P. R. Barber, B. Vojnovic, and D. J. Chaplin, “Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate: intravital microscopy and measurement of vascular permeability,” Cancer Res.61(17), 6413–6422 (2001).
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F. Winkler, S. V. Kozin, R. T. Tong, S. S. Chae, M. F. Booth, I. Garkavtsev, L. Xu, D. J. Hicklin, D. Fukumura, E. di Tomaso, L. L. Munn, and R. K. Jain, “Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases,” Cancer Cell6(6), 553–563 (2004).
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C. Malcontenti-Wilson, L. Chan, M. Nikfarjam, V. Muralidharan, and C. Christophi, “Vascular targeting agent Oxi4503 inhibits tumor growth in a colorectal liver metastases model,” J. Gastroenterol. Hepatol.23(7 Pt 2), e96–e104 (2008).
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Chan, L. S.

L. Nguyen, T. Fifis, C. Malcontenti-Wilson, L. S. Chan, P. N. Costa, M. Nikfarjam, V. Muralidharan, and C. Christophi, “Spatial morphological and molecular differences within solid tumors may contribute to the failure of vascular disruptive agent treatments,” BMC Cancer12(1), 522 (2012).
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J. A. Nagy, S. H. Chang, A. M. Dvorak, and H. F. Dvorak, “Why are tumour blood vessels abnormal and why is it important to know?” Br. J. Cancer100(6), 865–869 (2009).
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Chaplin, D. J.

Y. Z. Sheng, J. Y. Hua, K. G. Pinney, C. M. Garner, R. R. Kane, J. A. Prezioso, D. J. Chaplin, and K. Edvardsen, “Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis,” Int. J. Cancer111(4), 604–610 (2004).
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J. Y. Hua, Y. Z. Sheng, K. G. Pinney, C. M. Garner, R. R. Kane, J. A. Prezioso, G. R. Pettit, D. J. Chaplin, and K. Edvardsen, “Oxi4503, a novel vascular targeting agent: Effects on blood flow and antitumor activity in comparison to combretastatin A-4 phosphate,” Anticancer Res.23(2B), 1433–1440 (2003).
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G. M. Tozer, V. E. Prise, J. Wilson, M. Cemazar, S. Shan, M. W. Dewhirst, P. R. Barber, B. Vojnovic, and D. J. Chaplin, “Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate: intravital microscopy and measurement of vascular permeability,” Cancer Res.61(17), 6413–6422 (2001).
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A. N. Fontanella, T. Schroeder, D. W. Hochman, R. E. Chen, G. Hanna, M. M. Haglund, T. W. Secomb, G. M. Palmer, and M. W. Dewhirst, “Quantitative mapping of hemodynamics in the lung, brain, and dorsal window chamber-grown tumors using a novel, automated algorithm,” Microcirculation20(8), 724–735 (2013).
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J. H. Tai, J. Tessier, A. J. Ryan, L. Hoffman, X. Chen, and T. Y. Lee, “Assessment of acute antivascular effects of vandetanib with high-resolution dynamic contrast-enhanced computed tomographic imaging in a human colon tumor xenograft model in the nude rat,” Neoplasia12(9), 697–707 (2010).
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Chilkoti, A.

M. R. Dreher, W. G. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti, “Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers,” J. Natl. Cancer Inst.98(5), 335–344 (2006).
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Choi, B.

A. J. Moy, S. M. White, E. S. Indrawan, J. Lotfi, M. J. Nudelman, S. J. Costantini, N. Agarwal, W. Jia, K. M. Kelly, B. S. Sorg, and B. Choi, “Wide-field functional imaging of blood flow and hemoglobin oxygen saturation in the rodent dorsal window chamber,” Microvasc. Res.82(3), 199–209 (2011).
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S. Matsumoto, S. Batra, K. Saito, H. Yasui, R. Choudhuri, C. Gadisetti, S. Subramanian, N. Devasahayam, J. P. Munasinghe, J. B. Mitchell, and M. C. Krishna, “Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia,” Cancer Res.71(20), 6350–6359 (2011).
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Choyke, P. L.

D. M. McDonald and P. L. Choyke, “Imaging of angiogenesis: from microscope to clinic,” Nat. Med.9(6), 713–725 (2003).
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J. G. Christensen, “A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities,” Ann. Oncol.18(Suppl 10), x3–x10 (2007).
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L. Nguyen, T. Fifis, C. Malcontenti-Wilson, L. S. Chan, P. N. Costa, M. Nikfarjam, V. Muralidharan, and C. Christophi, “Spatial morphological and molecular differences within solid tumors may contribute to the failure of vascular disruptive agent treatments,” BMC Cancer12(1), 522 (2012).
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C. Malcontenti-Wilson, L. Chan, M. Nikfarjam, V. Muralidharan, and C. Christophi, “Vascular targeting agent Oxi4503 inhibits tumor growth in a colorectal liver metastases model,” J. Gastroenterol. Hepatol.23(7 Pt 2), e96–e104 (2008).
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G. J. Madlambayan, A. M. Meacham, K. Hosaka, S. Mir, M. Jorgensen, E. W. Scott, D. W. Siemann, and C. R. Cogle, “Leukemia regression by vascular disruption and antiangiogenic therapy,” Blood116(9), 1539–1547 (2010).
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L. Nguyen, T. Fifis, C. Malcontenti-Wilson, L. S. Chan, P. N. Costa, M. Nikfarjam, V. Muralidharan, and C. Christophi, “Spatial morphological and molecular differences within solid tumors may contribute to the failure of vascular disruptive agent treatments,” BMC Cancer12(1), 522 (2012).
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A. J. Moy, S. M. White, E. S. Indrawan, J. Lotfi, M. J. Nudelman, S. J. Costantini, N. Agarwal, W. Jia, K. M. Kelly, B. S. Sorg, and B. Choi, “Wide-field functional imaging of blood flow and hemoglobin oxygen saturation in the rodent dorsal window chamber,” Microvasc. Res.82(3), 199–209 (2011).
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G. M. Tozer, S. Akerman, N. A. Cross, P. R. Barber, M. A. Björndahl, O. Greco, S. Harris, S. A. Hill, D. J. Honess, C. R. Ireson, K. L. Pettyjohn, V. E. Prise, C. C. Reyes-Aldasoro, C. Ruhrberg, D. T. Shima, and C. Kanthou, “Blood vessel maturation and response to vascular-disrupting therapy in single vascular endothelial growth factor-A isoform-producing tumors,” Cancer Res.68(7), 2301–2311 (2008).
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M. Wankhede, C. Dedeugd, D. W. Siemann, and B. S. Sorg, “In vivo functional differences in microvascular response of 4T1 and Caki-1 tumors after treatment with OXi4503,” Oncol. Rep.23(3), 685–692 (2010).
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M. Czabanka, M. Vinci, F. Heppner, A. Ullrich, and P. Vajkoczy, “Effects of sunitinib on tumor hemodynamics and delivery of chemotherapy,” Int. J. Cancer124(6), 1293–1300 (2009).
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B. J. Vakoc, D. Fukumura, R. K. Jain, and B. E. Bouma, “Cancer imaging by optical coherence tomography: preclinical progress and clinical potential,” Nat. Rev. Cancer12(5), 363–368 (2012).
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M. Taylor, F. Billiot, V. Marty, V. Rouffiac, P. Cohen, E. Tournay, P. Opolon, F. Louache, G. Vassal, C. Laplace-Builhé, P. Vielh, J. C. Soria, and F. Farace, “Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells,” Cancer Discov.2(5), 434–449 (2012).
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M. Taylor, F. Billiot, V. Marty, V. Rouffiac, P. Cohen, E. Tournay, P. Opolon, F. Louache, G. Vassal, C. Laplace-Builhé, P. Vielh, J. C. Soria, and F. Farace, “Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells,” Cancer Discov.2(5), 434–449 (2012).
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M. Czabanka, M. Vinci, F. Heppner, A. Ullrich, and P. Vajkoczy, “Effects of sunitinib on tumor hemodynamics and delivery of chemotherapy,” Int. J. Cancer124(6), 1293–1300 (2009).
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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.81(Spec No 1), S12–S20 (2008).
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M. Wankhede, C. Dedeugd, D. W. Siemann, and B. S. Sorg, “In vivo functional differences in microvascular response of 4T1 and Caki-1 tumors after treatment with OXi4503,” Oncol. Rep.23(3), 685–692 (2010).
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T. Nielsen, T. Wittenborn, and M. R. Horsman, “Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in preclinical studies of antivascular treatments,” Pharmaceutics4(4), 563–589 (2012).
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F. Winkler, S. V. Kozin, R. T. Tong, S. S. Chae, M. F. Booth, I. Garkavtsev, L. Xu, D. J. Hicklin, D. Fukumura, E. di Tomaso, L. L. Munn, and R. K. Jain, “Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases,” Cancer Cell6(6), 553–563 (2004).
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G. G. Hillman, V. Singh-Gupta, H. Zhang, A. K. Al-Bashir, Y. Katkuri, M. Li, C. K. Yunker, A. D. Patel, J. Abrams, and E. M. Haacke, “Dynamic Contrast-Enhanced Magnetic Resonance Imaging of Vascular Changes Induced by Sunitinib in Papillary Renal Cell Carcinoma Xenograft Tumors,” Neoplasia11(9), 910–920 (2009).
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G. G. Hillman, V. Singh-Gupta, H. Zhang, A. K. Al-Bashir, Y. Katkuri, M. Li, C. K. Yunker, A. D. Patel, J. Abrams, and E. M. Haacke, “Dynamic Contrast-Enhanced Magnetic Resonance Imaging of Vascular Changes Induced by Sunitinib in Papillary Renal Cell Carcinoma Xenograft Tumors,” Neoplasia11(9), 910–920 (2009).
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K. L. Osusky, D. E. Hallahan, A. Fu, F. Ye, Y. Shyr, and L. Geng, “The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation, and blood vessel formation in vivo, but has little effect on existing tumor vessels,” Angiogenesis7(3), 225–233 (2004).
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D. W. Siemann and W. Y. Shi, “Dual targeting of tumor vasculature: Combining avastin and vascular disrupting agents (CA4P or OXi4503),” Anticancer Res.28(4B), 2027–2031 (2008).
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S. Dufort, L. Sancey, C. Wenk, V. Josserand, and J. L. Coll, “Optical small animal imaging in the drug discovery process,” Biochim. Biophys. Acta1798(12), 2266–2273 (2010).
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Biophys. J. (1)

R. D. Shonat, E. S. Wachman, W. H. Niu, A. P. Koretsky, and D. L. Farkas, “Near-simultaneous hemoglobin saturation and oxygen tension maps in mouse brain using an AOTF microscope,” Biophys. J.73(3), 1223–1231 (1997).
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Blood (1)

G. J. Madlambayan, A. M. Meacham, K. Hosaka, S. Mir, M. Jorgensen, E. W. Scott, D. W. Siemann, and C. R. Cogle, “Leukemia regression by vascular disruption and antiangiogenic therapy,” Blood116(9), 1539–1547 (2010).
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BMC Cancer (2)

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Br. J. Radiol. (1)

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.81(Spec No 1), S12–S20 (2008).
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Cancer (1)

A. D. Yang, T. W. Bauer, E. R. Camp, R. Somcio, W. B. Liu, F. Fan, and L. M. Ellis, “Improving delivery of antineoplastic agents with anti-vascular endothelial growth factor therapy,” Cancer103(8), 1561–1570 (2005).
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Cancer Cell (1)

F. Winkler, S. V. Kozin, R. T. Tong, S. S. Chae, M. F. Booth, I. Garkavtsev, L. Xu, D. J. Hicklin, D. Fukumura, E. di Tomaso, L. L. Munn, and R. K. Jain, “Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases,” Cancer Cell6(6), 553–563 (2004).
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Cancer Discov. (1)

M. Taylor, F. Billiot, V. Marty, V. Rouffiac, P. Cohen, E. Tournay, P. Opolon, F. Louache, G. Vassal, C. Laplace-Builhé, P. Vielh, J. C. Soria, and F. Farace, “Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells,” Cancer Discov.2(5), 434–449 (2012).
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Cancer Res. (4)

G. M. Tozer, V. E. Prise, J. Wilson, M. Cemazar, S. Shan, M. W. Dewhirst, P. R. Barber, B. Vojnovic, and D. J. Chaplin, “Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate: intravital microscopy and measurement of vascular permeability,” Cancer Res.61(17), 6413–6422 (2001).
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S. Matsumoto, S. Batra, K. Saito, H. Yasui, R. Choudhuri, C. Gadisetti, S. Subramanian, N. Devasahayam, J. P. Munasinghe, J. B. Mitchell, and M. C. Krishna, “Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia,” Cancer Res.71(20), 6350–6359 (2011).
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Clin. Cancer Res. (6)

P. E. Thorpe, “Vascular targeting agents as cancer therapeutics,” Clin. Cancer Res.10(2), 415–427 (2004).
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D. W. Siemann, M. C. Bibby, G. G. Dark, A. P. Dicker, F. A. L. M. Eskens, M. R. Horsman, D. Marmé, and P. M. Lorusso, “Differentiation and definition of vascular-targeted therapies,” Clin. Cancer Res.11(2 Pt 1), 416–420 (2005).
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V. Moreno Garcia, B. Basu, L. R. Molife, and S. B. Kaye, “Combining antiangiogenics to overcome resistance: rationale and clinical experience,” Clin. Cancer Res.18(14), 3750–3761 (2012).
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In Vivo (1)

W. Y. Shi and D. W. Siemann, “Targeting the tumor vasculature: Enhancing antitumor efficacy through combination treatment with ZD6126 and ZD6474,” In Vivo19(6), 1045–1050 (2005).
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Int. J. Cancer (2)

Y. Z. Sheng, J. Y. Hua, K. G. Pinney, C. M. Garner, R. R. Kane, J. A. Prezioso, D. J. Chaplin, and K. Edvardsen, “Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis,” Int. J. Cancer111(4), 604–610 (2004).
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M. Czabanka, M. Vinci, F. Heppner, A. Ullrich, and P. Vajkoczy, “Effects of sunitinib on tumor hemodynamics and delivery of chemotherapy,” Int. J. Cancer124(6), 1293–1300 (2009).
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Int. J. Radiat. Oncol. Biol. Phys. (1)

D. W. Siemann and W. Y. Shi, “Efficacy of combined antiangiogenic and vascular disrupting agents in treatment of solid tumors,” Int. J. Radiat. Oncol. Biol. Phys.60(4), 1233–1240 (2004).
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J. Biomed. Opt. (2)

B. S. Sorg, B. J. Moeller, O. Donovan, Y. T. Cao, and M. W. Dewhirst, “Hyperspectral imaging of hemoglobin saturation in tumor microvasculature and tumor hypoxia development,” J. Biomed. Opt.10(4), 044004 (2005).
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J. Clin. Oncol. (1)

H. L. Anderson, J. T. Yap, M. P. Miller, A. Robbins, T. Jones, and P. M. Price, “Assessment of pharmacodynamic vascular response in a phase I trial of combretastatin A4 phosphate,” J. Clin. Oncol.21(15), 2823–2830 (2003).
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J. Gastroenterol. Hepatol. (1)

C. Malcontenti-Wilson, L. Chan, M. Nikfarjam, V. Muralidharan, and C. Christophi, “Vascular targeting agent Oxi4503 inhibits tumor growth in a colorectal liver metastases model,” J. Gastroenterol. Hepatol.23(7 Pt 2), e96–e104 (2008).
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J. Mol. Biol. (1)

A. D. Bangham, M. M. Standish, and J. C. Watkins, “Diffusion of Univalent Ions Across the Lamellae of Swollen Phospholipids,” J. Mol. Biol.13(1), 238–252 (1965).
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J. Natl. Cancer Inst. (1)

M. R. Dreher, W. G. Liu, C. R. Michelich, M. W. Dewhirst, F. Yuan, and A. Chilkoti, “Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers,” J. Natl. Cancer Inst.98(5), 335–344 (2006).
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M. J. Machado and C. A. Mitchell, “Temporal changes in microvessel leakiness during wound healing discriminated by in vivo fluorescence recovery after photobleaching,” J. Physiol.589(19), 4681–4696 (2011).
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Microcirculation (1)

A. N. Fontanella, T. Schroeder, D. W. Hochman, R. E. Chen, G. Hanna, M. M. Haglund, T. W. Secomb, G. M. Palmer, and M. W. Dewhirst, “Quantitative mapping of hemodynamics in the lung, brain, and dorsal window chamber-grown tumors using a novel, automated algorithm,” Microcirculation20(8), 724–735 (2013).
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Microvasc. Res. (2)

A. J. Moy, S. M. White, E. S. Indrawan, J. Lotfi, M. J. Nudelman, S. J. Costantini, N. Agarwal, W. Jia, K. M. Kelly, B. S. Sorg, and B. Choi, “Wide-field functional imaging of blood flow and hemoglobin oxygen saturation in the rodent dorsal window chamber,” Microvasc. Res.82(3), 199–209 (2011).
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G. M. Palmer, A. N. Fontanella, S. Shan, G. Hanna, G. Zhang, C. L. Fraser, and M. W. Dewhirst, “In vivo optical molecular imaging and analysis in mice using dorsal window chamber models applied to hypoxia, vasculature and fluorescent reporters,” Nat. Protoc.6(9), 1355–1366 (2011).
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Nat. Rev. Cancer (1)

B. J. Vakoc, D. Fukumura, R. K. Jain, and B. E. Bouma, “Cancer imaging by optical coherence tomography: preclinical progress and clinical potential,” Nat. Rev. Cancer12(5), 363–368 (2012).
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Neoplasia (3)

J. V. Gaustad, K. G. Brurberg, T. G. Simonsen, C. S. Mollatt, and E. K. Rofstad, “Tumor vascularity assessed by magnetic resonance imaging and intravital microscopy imaging,” Neoplasia10(4), 354–362 (2008).
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G. G. Hillman, V. Singh-Gupta, H. Zhang, A. K. Al-Bashir, Y. Katkuri, M. Li, C. K. Yunker, A. D. Patel, J. Abrams, and E. M. Haacke, “Dynamic Contrast-Enhanced Magnetic Resonance Imaging of Vascular Changes Induced by Sunitinib in Papillary Renal Cell Carcinoma Xenograft Tumors,” Neoplasia11(9), 910–920 (2009).
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Oncol. Rep. (1)

M. Wankhede, C. Dedeugd, D. W. Siemann, and B. S. Sorg, “In vivo functional differences in microvascular response of 4T1 and Caki-1 tumors after treatment with OXi4503,” Oncol. Rep.23(3), 685–692 (2010).
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Opt. Lett. (2)

Pharmaceutics (1)

T. Nielsen, T. Wittenborn, and M. R. Horsman, “Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in preclinical studies of antivascular treatments,” Pharmaceutics4(4), 563–589 (2012).
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PLoS ONE (1)

R. T. Ullrich, J. F. Jikeli, M. Diedenhofen, P. Böhm-Sturm, M. Unruh, S. Vollmar, and M. Hoehn, “In-vivo visualization of tumor microvessel density and response to anti-angiogenic treatment by high resolution MRI in mice,” PLoS ONE6(5), e19592 (2011).
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Figures (9)

Fig. 1
Fig. 1

Tumor volume measurement. (a) Front view of an installed window chamber with tumor outlined in black. (b) Back side of window chamber with tumor nodule outlined. The red lines indicate the measured length and width of the tumor nodule. (c) The height is measured as the distance the tumor nodule protrudes from the back of the window chamber, indicated by the red line.

Fig. 2
Fig. 2

Hyperspectral imaging of hemoglobin saturation. Sixteen brightfield images are acquired at 5 nm intervals from 500 nm to 575 nm. Using a previously determined linear least squares regression model, a pseudocolor map of hemoglobin saturation is created in MATLAB®.

Fig. 3
Fig. 3

First-pass fluorescence imaging. Fluorescent liposomes are injected and simultaneously recorded as the liposomes first enter the field of view. Frame (1) represents ~1.9 s after injection of liposomes, (2) ~5.8 s, (3) ~7.7s, (4) ~11.6 s, (5) ~19.3s and (6) ~30.8 s. MATLAB® is then used to create a vascular mask of the vessel area and assign BSTs to each pixel in the vascular mask. The BST is defined as the time it takes to reach the average pixel intensity for each individual pixel in the vascular mask. In the final BST map, red corresponds to faster BSTs and blue longer BSTs.

Fig. 4
Fig. 4

Daily tumor volume measurements of tumor nodules in window chambers (median ± interquartile range). All treatment groups showed tumor growth delay compared to controls (p<0.01), but combination treatment showed significantly greater tumor volume suppression in comparison to the OXi4503 (p<0.01) and Sunitinib (p<0.001) single agent groups.

Fig. 5
Fig. 5

Daily brightfield images of a representative tumor from the untreated control, OXi4503 only, Sunitinib only and combination treated groups over 7 days (field of view; 3.1mm width x 3.1 mm height).

Fig. 6
Fig. 6

Immunohistologic analysis of tumor vasculature. (a) Harvested tumor slices (5 μm) were labeled with MECA-32 (red) for endothelial cells and DAPI (blue) for cell nuclei. Images were taken at 20x (scalebar = 140 µm). (b) MECA-32/DAPI ratio analysis of 10 regions per tumor for control (n = 5), OXi4503 (n = 4), Sunitinib (n = 4) and combination treatments (n = 4). The median is indicated. All three treatment groups had significantly less MECA-32 signal in comparison to controls (p<0.001). While there was no significant difference between OXi4503 and combination treated tumors, both OXi4503 (p<0.01) and combination (p<0.001) treated tumors had greater ratios in comparison to Sunitinib.

Fig. 7
Fig. 7

Hb saturation and BST maps over time. In control tumors, BSTs became longer and oxygenation decreased as complicated vessel pathways formed. OXi4503 treated tumors displayed vascular damage up to the rim of the tumor after initial treatment, resulting in neovascualture in the tumor periphery with faster BSTs and a higher oxygenation (day 3). Each subsequent treatment was less effective, leaving larger vascular rims with greater variation in BSTs and oxygenation, resembling that of control tumor vessels. Sunitinib treated tumor vessels exhibited faster, more homogenous BSTs with higher oxygenation values that were maintained. The combination treatment left no tumor vessels to be analyzed.

Fig. 8
Fig. 8

Scatter plots correlating the Hb saturation and BST value of 30 specific vessel regions of interest in tumors shown in Fig. 7. The control tumor resulted in longer BSTs and lower Hb saturation values. OXi4503 suppressed this trend initially on day 3, but began to develop BST and Hb saturation values similar to the control tumor by day 7. The Sunitinib treated tumor showed inhibition of long blood supply times and maintenance of Hb saturation values. It is important to note that the values associated with the combination treated tumor correspond to normal vessels surrounding the tumor since all detectable tumor vessels were eradicated.

Fig. 9
Fig. 9

Average BST, Hb saturation and vessel density for each treatment group over time. Analysis was performed on the entire visible tumor area (average ± SEM). Each drug group was shown to significantly suppress increases in BST, decreases in Hb saturation and increases in vessel density seen in control tumors by day 7 (p<0.05).

Equations (1)

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Tumor volume= 1 2 [ π 6 ×length×width×height ]

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