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Advances in Brief |
1 E. L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; 2 The Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, Massachusetts; and 3 ImClone Systems, Incorporated, New York, New York
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Introduction |
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Materials and Methods |
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DC101 Treatment.
DC101 (ImClone Systems Inc., New York, NY) was administered i.p. at a dose of 40 mg/kg, previously determined to have antitumor effects in vivo (10)
. The control group received 40 mg/kg, i.p of nonspecific rat IgG1 antibody (ImClone). All of the experiments were done 3 days after the injection of DC101 (IgG for the control), unless otherwise noted.
Functional Lymphatic Assay.
To identify the functional lymphatic vessels in tumors, ferritin microlymphangiography and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) immunostaining were performed according to published methods (6)
.
Intravital Microscopy.
To visualize functional blood vessels in MCaIV or LS174T in the dorsal chamber of SCID mice in vivo, fluorescein-labeled dextran (Mr 2,000,000; Sigma) was injected i.v. (11)
. Vascular length per unit area and vessel mean diameter were obtained by averaging measurements over six random regions per mouse. The effective vascular permeability was measured using cyanine-5-labeled BSA as described previously (12)
. For multiphoton microscopy images, maximum intensity projections of stacked images were done offline using Confocal Assistant.
Immunostaining of Collagen IV.
MCaIV-tumor-bearing mice (n = 6 in control group; n = 5 in DC101-treated group) were injected with FITC-CD31 1 h before perfusing fixative. The mice were perfused and fixed with 4% paraformaldehyde, and 100-µm-thick sections were prepared (13)
. Collagen IV (Chemicon) was stained overnight; and tetramethyl rhodamine isothiocyanate (TRITC) goat antirabbit antibody was used as a secondary antibody. Three images per section were taken by confocal microscopy. Total vessel length and the length of segments covered by collagen IV were traced in three random regions (each region was 700 µm by 700 µm) for each 100-µm-thick section. On average, 
50 vessel segments were measured per mouse.
Immunostaining of 
SMA.
Similarly, MCaIV-tumor-bearing mice (n = 4) were given injections of FITC-CD31 and were perfused and fixed with 4% paraformaldehyde, and 100-µm-thick sections were prepared. Anti--smooth muscle actin (SMA; Cy-3-conjugated mouse monoclonal, clone 1A4; Sigma) antibody was used to identify SMA-positive perivascular cells. The tissue sections were examined using a confocal microscope. Quantification was performed in a manner similar to collagen IV staining.
IFP Measurements with the Wick-in-Needle Technique.
IFP was measured with the wick-in-needle technique (14)
prior to and during DC101/control antibody treatment for 54A and U87. DC101/control antibodies were injected once every 3 days. For each time point, IFP was measured in at least two different tumor regions.
MVP and IFP Measurements with the Micropipette Technique.
MCaIV tumors were implanted in the dorsal skinfold chamber of SCID mice as described previously (15)
. The dorsal skinfold chamber preparation provides a stable and easy access for IFP and MVP measurements with the micropipette technique (8
, 16)
. For each mouse, two to seven IFP and MVP measurements were obtained. Under stereomicroscopic guidance, micropipettes with an opening of 2.5 µm were inserted inside blood vessels to measure the MVP (confirmed by Lissamine Green B injection). The IFPs were generally measured at 0.5–1 mm from the tumor surface.
Oncotic Pressure Measurements.
The chronic wick technique was used to collect tumor interstitial fluid (9)
. A long wick (5 cm) was transplanted together with the MCaIV tumors and was collected postmortem 2 weeks later; interstitial fluid was obtained by centrifugation. A membrane colloid osmometer with ultrafiltration membranes (Amicon PM10; Millipore Corp., Bedford, MA) was used to measure oncotic pressure.
Extravasation of TRITC-BSA.
TRITC-BSA (0.1 ml; Molecular Probes) was injected i.v. 1 h before perfusion fixation in tumor-bearing mice. Biotinylated lectin was also injected 5 min before fixation. Three 10-µm-thick frozen sections, 50 µm apart, were prepared from each tumor block. Images were taken using two-photon microscopy. Perfused biotinylated lectin was used to identify functional vessels, and extravasation pattern of TRITC-BSA was analyzed using a program written in ImageJ. Ten concentric rings of 3.25-µm thickness were drawn starting at the vessel wall. Average intensity was calculated within each ring, and the intensity profile was fitted to an exponential function (I = Ae–x/L + C, where I = pixel intensity, x = distance from vessels, and L = characteristic penetration length). The characteristic penetration length was compared between the two treatment groups.
Statistical Analysis.
Data are presented as mean ± SE. Significant differences between groups were determined with a Student’s t test (JMP Program). P < 0.05 was considered statistically significant.
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Results |
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, and human glioblastoma multiforme U87 xenografts (Fig. 1B)
. At the same time, we did not find any evidence of functional lymphatic vessels in the tumors of either treated or control animals (Fig. 1C)
. Thus, the drop in IFP could not be attributed to modifications in lymphatic function.
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; Fig. 2, A and B
). To obtain further insight into the dynamic changes occurring in the tumor vasculature, we continuously monitored the same region of the tumor over 6 consecutive days using two-photon microscopy. This technique allowed us to image up to 200 µm deep with 1-µm resolution (11)
. In contrast to skeletal muscle, which has an organized vasculature with a relatively smooth vascular wall and uniform diameter (Fig. 2C)
, untreated MCaIV tumors had tortuous vessels with abrupt changes in vessel diameter (arrowheads in Fig. 2D
). On the basis of the dynamic high resolution images, the surprising finding was that, 2–3 days after DC101 treatment, many of these vessels also became less tortuous besides getting smaller in diameter (arrow in Fig. 2E
). By day 5, in some regions, some of these vessels regressed completely. Furthermore, the vessels at the tumor–host interface also became less tortuous and assumed a relatively normal morphology (Fig. 2F)
. Similar striking vascular changes were also observed in the human colon adenocarcinoma LS174T (Fig. 2, G and H)
. Thus, DC101 "normalizes" the architecture of the vascular network before complete regression.
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SMA (which label basement membrane and mural cells, respectively). Unlike the vessels in normal muscle, the collagen IV staining around some vessels was below the detection limit in MCaIV tumors (Fig. 3A)
. Consistent with normalization, more vessels exhibited collagen IV staining after DC101 treatment (Fig. 3, B and C)
. DC101 also significantly increased the fractional coverage of tumor blood vessels by SMA-positive cells (Fig. 3D)
. Approximately 25% of the vessels in untreated tumors had little or no perivascular cell coverage, but this fraction dropped to 8% after DC101 treatment (P < 0.005). Thus, DC101 induces structural normalization of the tumor vasculature by homogenizing the vessel size, reducing vessel tortuosity, and increasing the fractional coverage of the vascular endothelium by perivascular cells and basement membrane.
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. In general, leaky vessels in tumors lead to an increase in the interstitial oncotic pressure (9)
, which becomes approximately equal to the plasma oncotic pressure. We found that in DC101-treated tumors the interstitial oncotic pressure was significantly lower than in the control group (Fig. 3E)
, whereas the plasma oncotic pressure did not change. This decrease in interstitial oncotic pressure is consistent with the decrease in vascular permeability to macromolecules induced by DC101. The enhanced oncotic pressure gradient across the vasculature is another hallmark of tumor vasculature normalization.
DC101 Induces a Hydrostatic Pressure Gradient Across the Tumor Vasculature.
In solid tumors, MVP is approximately equal to IFP, leading to nearly zero pressure difference across the vessel wall (8)
. As a matter of fact, these two pressures are so closely coupled that changing the vascular pressure leads to similar changes in the IFP within seconds, until they both become equal again (20)
. Thus the DC101-induced decrease in IFP might be accompanied by a similar decrease in MVP. To test this, we measured MVP in control and DC101-treated tumors by directly inserting micropipettes in MCaIV tumor vessels (16)
. We found that MVP was unaffected by DC101 treatment (Fig. 3F)
. Thus, DC101 creates a sustained hydrostatic pressure gradient across the vasculature.
DC101 Increases BSA Penetration in Tumors.
Movement of molecules across vessel walls occurs by diffusion and convection. Diffusion is governed by concentration gradients across the vessel wall, whereas convection is governed by pressure gradients. To test whether the pressure gradient across the vascular wall improves the penetration of large molecules, we injected fluorescently-labeled BSA i.v. into MCaIV-tumor-bearing mice and observed the pattern of BSA extravasation. We also identified functional blood vessels using biotinylated lectin. Quantitative analysis confirmed that DC101 produced a significantly deeper penetration of BSA molecules into the tumor (Fig. 4, A–E)
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Discussion |
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. This result implies that vessels with less mural cell coverage are more vulnerable to DC101-induced regression, which is consistent with previous findings that tumor vessels without mural cells tend to regress after VEGF withdrawal (21)
. Our functional data demonstrate for the first time that a drop in vascular permeability induces transvascular gradients in oncotic and hydrostatic pressure in tumors. The induced hydrostatic pressure gradient improves the penetration of large molecules into tumors.
In tumors, the abnormally high leakiness of the vasculature hinders drug delivery by inducing blood flow stasis (22
, 23)
, whereas normalized vessels are less leaky to macromolecules. However, the permeability of the normalized vasculature is still significantly higher than that of normal tissues (12
, 18)
. The small drop in oncotic pressure from 19 to 17 mm Hg induced by DC101 is also indirect evidence that the vascular permeability of DC101-treated MCaIV tumors is still elevated. For example, in s.c. tissue, the oncotic pressure is 8 mm Hg (9)
. The change in oncotic pressure associated with DC101 leads to a minor increase in the hydrostatic pressure gradient, which is sufficient to increase the transvascular convection of a macromolecule and is most likely responsible for the deeper penetration of albumin.
Fluid movement across the vascular wall can be described by Starling’s equation (18)
. Starling’s equation states that the rate of fluid movement across a unit area of vascular wall (Jv/A) is proportional to the net pressure difference across the vessel wall:
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p (plasma oncotic pressure) and i (interstitial oncotic pressure)]. The reflection coefficient, 
, determines the effectiveness of the oncotic pressure gradient across the vascular wall. The value of for albumin varies between 0 for the liver (with a high vascular permeability) and 1 for the impermeable brain vessels; lung has a of 0.5 (24
, 25)
. To our knowledge, the reflection coefficient of the tumor vasculature has not been measured. Because the tumor vasculature has relatively large pores (26)
and the oncotic pressure in the interstitium is similar to the oncotic pressure of plasma, the reflection coefficient is most likely close to 0. Based on the theory for hindered transport of rigid solutes, the calculated reflection coefficient for BSA is 0.0002 ( = [1 – [1 – radius of BSA (3.5 nm)/vessel pore size (500 nm)]2]2) (26)
. Thus, the increase in oncotic pressure gradient induced by DC101 has minimal effects on the transvascular flow. We have previously shown that angiotensin II can increase the systemic blood pressure in mice and can create a pressure gradient across the vessel wall in tumors (20) . Unfortunately, interstitial pressure catches up with vascular pressure, and the pressure gradient across the vessel wall dissipates in less than 1 min. Nevertheless, even these short-lived gradients can increase the delivery of specific antibodies in tumors (20) . Thus, the sustained hydrostatic pressure gradient across the tumor vasculature, induced by DC101, can increase the transvascular convection of large molecules, despite a drop in vascular permeability to macromolecules.
The original rationale for combining antiangiogenic and cytotoxic therapies was to target two distinct cell populations within solid tumors: cancer cells and endothelial cells. When endothelial cells are targeted, blood vessels should be destroyed, and, thus, the delivery of therapeutics is compromised. However, several preclinical studies clearly demonstrate that the delivery of therapeutics is not compromised by antiangiogenic agents (27) , and it even increases in some cases (28) . The vessel normalization and the restoration of pressure gradients induced by VEGF blockade may explain the increased uptake of cytotoxic agents in tumors. For a cytotoxic agent to be effective, it must reach all cancer cells and in effective quantities. Antiangiogenic therapy, as shown by this study, might facilitate a more uniform delivery of therapeutic agents to cancer cells, including those that are farther from the vessels. This mechanism might contribute to the potentiation of conventional therapies by antiangiogenic agents (1 , 10 , 28, 29, 30, 31) .
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Addendum |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Rakesh Jain, E. L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, COX 734, Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114. Phone: (617) 501-4083; Fax: (617) 724-1819; E-mail: jain{at}steele.mgh.harvard.edu
Received 1/ 9/04. Revised 3/18/04. Accepted 4/ 9/04.
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mechanism(s) of interaction). Cancer Metastasis Rev, 15: 247-72, 1996.[CrossRef][Medline]
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S. V. Kozin, F. Winkler, I. Garkavtsev, D. J. Hicklin, R. K. Jain, and Y. Boucher Human Tumor Xenografts Recurring after Radiotherapy Are More Sensitive to Anti-Vascular Endothelial Growth Factor Receptor-2 Treatment than Treatment-Naive Tumors Cancer Res., June 1, 2007; 67(11): 5076 - 5082. [Abstract] [Full Text] [PDF]
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R. K. Jain, R. T. Tong, and L. L. Munn Effect of Vascular Normalization by Antiangiogenic Therapy on Interstitial Hypertension, Peritumor Edema, and Lymphatic Metastasis: Insights from a Mathematical Model Cancer Res., March 15, 2007; 67(6): 2729 - 2735. [Abstract] [Full Text] [PDF]
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M. Jain, G. Venkatraman, and S. K. Batra Optimization of Radioimmunotherapy of Solid Tumors: Biological Impediments and Their Modulation Clin. Cancer Res., March 1, 2007; 13(5): 1374 - 1382. [Abstract] [Full Text] [PDF]
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J. J. Vredenburgh, A. Desjardins, J. E. Herndon II, J. M. Dowell, D. A. Reardon, J. A. Quinn, J. N. Rich, S. Sathornsumetee, S. Gururangan, M. Wagner, et al. Phase II Trial of Bevacizumab and Irinotecan in Recurrent Malignant Glioma Clin. Cancer Res., February 15, 2007; 13(4): 1253 - 1259. [Abstract] [Full Text] [PDF]
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K. J. Williams, B. A. Telfer, A. M. Shannon, M. Babur, I. J. Stratford, and S. R. Wedge Combining radiotherapy with AZD2171, a potent inhibitor of vascular endothelial growth factor signaling: pathophysiologic effects and therapeutic benefit Mol. Cancer Ther., February 1, 2007; 6(2): 599 - 606. [Abstract] [Full Text] [PDF]
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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]
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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]
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M. Muruganandham, M. Lupu, J. P. Dyke, C. Matei, M. Linn, K. Packman, K. Kolinsky, B. Higgins, and J. A. Koutcher Preclinical evaluation of tumor microvascular response to a novel antiangiogenic/antitumor agent RO0281501 by dynamic contrast-enhanced MRI at 1.5 T. Mol. Cancer Ther., August 1, 2006; 5(8): 1950 - 1957. [Abstract] [Full Text] [PDF]
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B. Dome, J. Timar, J. Dobos, L. Meszaros, E. Raso, S. Paku, I. Kenessey, G. Ostoros, M. Magyar, A. Ladanyi, et al. Identification and clinical significance of circulating endothelial progenitor cells in human non-small cell lung cancer. Cancer Res., July 15, 2006; 66(14): 7341 - 7347. [Abstract] [Full Text] [PDF]
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S. Jones-Bolin, H. Zhao, K. Hunter, A. Klein-Szanto, and B. Ruggeri The effects of the oral, pan-VEGF-R kinase inhibitor CEP-7055 and chemotherapy in orthotopic models of glioblastoma and colon carcinoma in mice. Mol. Cancer Ther., July 1, 2006; 5(7): 1744 - 1753. [Abstract] [Full Text] [PDF]
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D. G. Duda Antiangiogenesis and drug delivery to tumors: bench to bedside and back. Cancer Res., April 15, 2006; 66(8): 3967 - 3970. [Abstract] [Full Text] [PDF]
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Y. Hassid, E. Furman-Haran, R. Margalit, R. Eilam, and H. Degani Noninvasive magnetic resonance imaging of transport and interstitial fluid pressure in ectopic human lung tumors. Cancer Res., April 15, 2006; 66(8): 4159 - 4166. [Abstract] [Full Text] [PDF]
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E. R. Camp, A. Yang, W. Liu, F. Fan, R. Somcio, D. J. Hicklin, and L. M. Ellis Roles of Nitric Oxide Synthase Inhibition and Vascular Endothelial Growth Factor Receptor-2 Inhibition on Vascular Morphology and Function in an In vivo Model of Pancreatic Cancer Clin. Cancer Res., April 15, 2006; 12(8): 2628 - 2633. [Abstract] [Full Text] [PDF]
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J. Hagendoorn, R. Tong, D. Fukumura, Q. Lin, J. Lobo, T. P. Padera, L. Xu, R. Kucherlapati, and R. K. Jain Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis. Cancer Res., April 1, 2006; 66(7): 3360 - 3364. [Abstract] [Full Text] [PDF]
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T. Nakahara, S. M. Norberg, D. R. Shalinsky, D. D. Hu-Lowe, and D. M. McDonald Effect of Inhibition of Vascular Endothelial Growth Factor Signaling on Distribution of Extravasated Antibodies in Tumors Cancer Res., February 1, 2006; 66(3): 1434 - 1445. [Abstract] [Full Text] [PDF]
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A. J. Primeau, A. Rendon, D. Hedley, L. Lilge, and I. F. Tannock The Distribution of the Anticancer Drug Doxorubicin in Relation to Blood Vessels in Solid Tumors Clin. Cancer Res., December 15, 2005; 11(24): 8782 - 8788. [Abstract] [Full Text] [PDF]
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K. Yokoi, T. Sasaki, C. D. Bucana, D. Fan, C. H. Baker, Y. Kitadai, T. Kuwai, J. L. Abbruzzese, and I. J. Fidler Simultaneous Inhibition of EGFR, VEGFR, and Platelet-Derived Growth Factor Receptor Signaling Combined with Gemcitabine Produces Therapy of Human Pancreatic Carcinoma and Prolongs Survival in an Orthotopic Nude Mouse Model Cancer Res., November 15, 2005; 65(22): 10371 - 10380. [Abstract] [Full Text] [PDF]
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R. D. Loberg, C. J. Logothetis, E. T. Keller, and K. J. Pienta Pathogenesis and Treatment of Prostate Cancer Bone Metastases: Targeting the Lethal Phenotype J. Clin. Oncol., November 10, 2005; 23(32): 8232 - 8241. [Abstract] [Full Text] [PDF]
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C. G. Willett, Y. Boucher, D. G. Duda, E. di Tomaso, L. L. Munn, R. T. Tong, S. V. Kozin, L. Petit, R. K. Jain, D. C. Chung, et al. Surrogate Markers for Antiangiogenic Therapy and Dose-Limiting Toxicities for Bevacizumab With Radiation and Chemotherapy: Continued Experience of a Phase I Trial in Rectal Cancer Patients J. Clin. Oncol., November 1, 2005; 23(31): 8136 - 8139. [Full Text] [PDF]
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 Z. Kan, S. Phongkitkarun, S. Kobayashi, Y. Tang, L. M. Ellis, T. Y. Lee, and C. Charnsangavej Functional CT for Quantifying Tumor Perfusion in Antiangiogenic Therapy in a Rat Model Radiology, October 1, 2005; 237(1): 151 - 158. [Abstract] [Full Text] [PDF]
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H. S. Rugo, R. S. Herbst, G. Liu, J. W. Park, M. S. Kies, H. M. Steinfeldt, Y. K. Pithavala, S. D. Reich, J. L. Freddo, and G. Wilding Phase I Trial of the Oral Antiangiogenesis Agent AG-013736 in Patients With Advanced Solid Tumors: Pharmacokinetic and Clinical Results J. Clin. Oncol., August 20, 2005; 23(24): 5474 - 5483. [Abstract] [Full Text] [PDF]
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P. H. Thaker, S. Yazici, M. B. Nilsson, K. Yokoi, R. Z. Tsan, J. He, S.-J. Kim, I. J. Fidler, and A. K. Sood Antivascular Therapy for Orthotopic Human Ovarian Carcinoma through Blockade of the Vascular Endothelial Growth Factor and Epidermal Growth Factor Receptors Clin. Cancer Res., July 1, 2005; 11(13): 4923 - 4933. [Abstract] [Full Text] [PDF]
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D. Zips, W. Eicheler, P. Geyer, F. Hessel, A. Dorfler, H. D. Thames, M. Haberey, and M. Baumann Enhanced Susceptibility of Irradiated Tumor Vessels to Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibition Cancer Res., June 15, 2005; 65(12): 5374 - 5379. [Abstract] [Full Text] [PDF]
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P. E. Huber, M. Bischof, J. Jenne, S. Heiland, P. Peschke, R. Saffrich, H.-J. Grone, J. Debus, K. E. Lipson, and A. Abdollahi Trimodal Cancer Treatment: Beneficial Effects of Combined Antiangiogenesis, Radiation, and Chemotherapy Cancer Res., May 1, 2005; 65(9): 3643 - 3655. [Abstract] [Full Text] [PDF]
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L. A. Khawli, P. Hu, and A. L. Epstein NHS76/PEP2, a Fully Human Vasopermeability-Enhancing Agent to Increase The Uptake and Efficacy of Cancer Chemotherapy Clin. Cancer Res., April 15, 2005; 11(8): 3084 - 3093. [Abstract] [Full Text] [PDF]
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L. M. Ellis Challenges in Translating Antiangiogenic Therapy from Bench to Bedside Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 74 - 77. [Full Text] [PDF]
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R. K. Jain Interstitial Transport in Tumors: Barriers and Strategies for Improvement Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 108 - 113. [Full Text] [PDF]
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S. S. Nathan, G. R. DiResta, J. E. Casas-Ganem, B. H. Hoang, R. Sowers, R. Yang, A. G. Huvos, R. Gorlick, and J. H. Healey Elevated Physiologic Tumor Pressure Promotes Proliferation and Chemosensitivity in Human Osteosarcoma Clin. Cancer Res., March 15, 2005; 11(6): 2389 - 2397. [Abstract] [Full Text] [PDF]
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S. Vosseler, N. Mirancea, P. Bohlen, M. M. Mueller, and N. E. Fusenig Angiogenesis Inhibition by Vascular Endothelial Growth Factor Receptor-2 Blockade Reduces Stromal Matrix Metalloproteinase Expression, Normalizes Stromal Tissue, and Reverts Epithelial Tumor Phenotype in Surface Heterotransplants Cancer Res., February 15, 2005; 65(4): 1294 - 1305. [Abstract] [Full Text] [PDF]
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D. J. Hicklin and L. M. Ellis Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis J. Clin. Oncol., February 10, 2005; 23(5): 1011 - 1027. [Abstract] [Full Text] [PDF]
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H.-P. Gerber and N. Ferrara Pharmacology and Pharmacodynamics of Bevacizumab as Monotherapy or in Combination with Cytotoxic Therapy in Preclinical Studies Cancer Res., February 1, 2005; 65(3): 671 - 680. [Abstract] [Full Text] [PDF]
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R. Ansiaux, C. Baudelet, B. F. Jordan, N. Beghein, P. Sonveaux, J. De Wever, P. Martinive, V. Gregoire, O. Feron, and B. Gallez Thalidomide Radiosensitizes Tumors through Early Changes in the Tumor Microenvironment Clin. Cancer Res., January 15, 2005; 11(2): 743 - 750. [Abstract] [Full Text] [PDF]
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 R. K. Jain Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy Science, January 7, 2005; 307(5706): 58 - 62. [Abstract] [Full Text] [PDF]
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, the control group; 
, the DC101 group. DC101 lowered the IFP in 54A tumors (A) and in U87 tumors (B) implanted s.c. in nude mice. Data are represented as mean ± SE. C, a lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1)-positive lymphatic vessel in the skeletal muscle adjacent to a MCaIV tumor (arrow). No LYVE-1-positive vessels were found inside the tumor in either the DC101 or the control group.
