This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Boucher, Y. Articles by Jain, R. K. Search for Related Content PubMed PubMed Citation Articles by Boucher, Y. Articles by Jain, R. K.

Interstitial Pressure Gradients in Tissue-isolated and Subcutaneous Tumors: Implications for Therapy¹

Tumor Microcirculation Laboratory, Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213-3890

High interstitial fluid pressure (IFP) in solid tumors is associated with reduced blood flow as well as inadequate delivery of therapeutic agents such as monoclonal antibodies. In the present study, IFP was measured as a function of radial position within two rat tissue-isolated tumors (mammary adenocarcinoma R3230AC, 0.4–1.9 g, n = 9, and Walker 256 carcinoma, 0.5–5.0 g, n = 6) and a s.c. tumor (mammary adenocarcinoma R3230AC, 0.6–20.0 g, n = 7). Micropipettes (tip diameters 2 to 4 µm) connected to a servo-null pressure-monitoring system were introduced to depths of 2.5 to 3.5 mm from the tumor surface and IFP was measured while the micropipettes were retrieved to the surface. The majority (86%) of the pressure profiles demonstrated a large gradient in the periphery leading to a plateau of almost uniform pressure in the deeper layers of the tumors. Within isolated tumors, pressures reached plateau values at a distance of 0.2 to 1.1 mm from the surface. In s.c. tumors the sharp increase began in skin and levelled off at the skin-tumor interface. These results demonstrate for the first time that the IFP is elevated throughout the tumor and drops precipitously to normal values in the tumor's periphery or in the immediately surrounding tissue. These results confirm the predictions of our recently published mathematical model of interstitial fluid transport in tumors (Jain and Baxter, Cancer Res., 48: 7022–7032, 1988), offer novel insight into the etiology of interstitial hypertension, and suggest possible strategies for improved delivery of therapeutic agents.

¹ Supported by the NCI (CA-36902) and NSF (CBT-88-16062). This work was presented at the American Institute of Chemical Engineers Annual Meeting in San Francisco, November 6–10, 1989; the Microcirculation Society Meeting in Washington, DC, March 31 to April 1, 1990; the Biomedical Engineering Society Meeting in Washington, DC, April 2–5, 1990; and the Radiation Research Society Annual Meeting in New Orleans, April 8–12, 1990.

² Recipient of Fonds de la Recherche en Santé du Quebéc Postdoctoral Fellowship (1988–1990).

³ Recipient of NSF Predoctoral Fellowship (1986–1989).

⁴ To whom requests for reprints should be addressed.

Received 12/12/89. Revised 4/ 2/90.

This article has been cited by other articles:

				S.-G. Yeo, J.-S. Kim, M.-J. Cho, K.-H. Kim, and J.-S. Kim Interstitial Fluid Pressure as a Prognostic Factor in Cervical Cancer Following Radiation Therapy Clin. Cancer Res., October 1, 2009; 15(19): 6201 - 6207. [Abstract] [Full Text] [PDF]

				N. Qayum, R. J. Muschel, J. H. Im, L. Balathasan, C. J. Koch, S. Patel, W. G. McKenna, and E. J. Bernhard Tumor Vascular Changes Mediated by Inhibition of Oncogenic Signaling Cancer Res., August 1, 2009; 69(15): 6347 - 6354. [Abstract] [Full Text] [PDF]

				D.-K. Chang, C.-Y. Chiu, S.-Y. Kuo, W.-C. Lin, A. Lo, Y.-P. Wang, P.-C. Li, and H.-C. Wu Antiangiogenic Targeting Liposomes Increase Therapeutic Efficacy for Solid Tumors J. Biol. Chem., May 8, 2009; 284(19): 12905 - 12916. [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. Khaibullina, B.-S. Jang, H. Sun, N. Le, S. Yu, V. Frenkel, J. A. Carrasquillo, I. Pastan, K. C.P. Li, and C. H. Paik Pulsed High-Intensity Focused Ultrasound Enhances Uptake of Radiolabeled Monoclonal Antibody to Human Epidermoid Tumor in Nude Mice J. Nucl. Med., February 1, 2008; 49(2): 295 - 302. [Abstract] [Full Text] [PDF]

				T.-Y. Lee, C.-T. Lin, S.-Y. Kuo, D.-K. Chang, and H.-C. Wu Peptide-Mediated Targeting to Tumor Blood Vessels of Lung Cancer for Drug Delivery Cancer Res., November 15, 2007; 67(22): 10958 - 10965. [Abstract] [Full Text] [PDF]

				E. R. Plimack, D. J. Stewart, and J.-P. J. Issa Combining Epigenetic and Cytotoxic Therapy in the Treatment of Solid Tumors J. Clin. Oncol., October 10, 2007; 25(29): 4519 - 4521. [Full Text] [PDF]

				O. Tredan, C. M. Galmarini, K. Patel, and I. F. Tannock Drug Resistance and the Solid Tumor Microenvironment J Natl Cancer Inst, October 3, 2007; 99(19): 1441 - 1454. [Abstract] [Full Text] [PDF]

				S. Dromi, V. Frenkel, A. Luk, B. Traughber, M. Angstadt, M. Bur, J. Poff, J. Xie, S. K. Libutti, K. C.P. Li, et al. Pulsed-High Intensity Focused Ultrasound and Low Temperature Sensitive Liposomes for Enhanced Targeted Drug Delivery and Antitumor Effect Clin. Cancer Res., May 1, 2007; 13(9): 2722 - 2727. [Abstract] [Full Text] [PDF]

				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]

				K. Sven and F. Josipa Interstitial Hydrostatic Pressure: a Manual for Students Advan Physiol Educ, March 1, 2007; 31(1): 116 - 117. [Full Text] [PDF]

				D. Simberg, T. Duza, J. H. Park, M. Essler, J. Pilch, L. Zhang, A. M. Derfus, M. Yang, R. M. Hoffman, S. Bhatia, et al. Biomimetic amplification of nanoparticle homing to tumors PNAS, January 16, 2007; 104(3): 932 - 936. [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. H. Alvarez, H. M. Kantarjian, and J. E. Cortes Biology of Platelet-Derived Growth Factor and Its Involvement in Disease Mayo Clin. Proc., September 1, 2006; 81(9): 1241 - 1257. [Abstract] [Full Text] [PDF]

				J. J. Lammerts van Bueren, W. K. Bleeker, H. O. Bogh, M. Houtkamp, J. Schuurman, J. G.J. van de Winkel, and P. W.H.I. Parren Effect of Target Dynamics on Pharmacokinetics of a Novel Therapeutic Antibody against the Epidermal Growth Factor Receptor: Implications for the Mechanisms of Action. Cancer Res., August 1, 2006; 66(15): 7630 - 7638. [Abstract] [Full Text] [PDF]

				Y. Navalitloha, E. S. Schwartz, E. N. Groothuis, C. V. Allen, R. M. Levy, and D. R. Groothuis Therapeutic implications of tumor interstitial fluid pressure in subcutaneous RG-2 tumors Neuro-oncol, July 1, 2006; 8(3): 227 - 233. [Abstract] [Full Text] [PDF]

				J. A. Ludwig, G. Szakacs, S. E. Martin, B. F. Chu, C. Cardarelli, Z. E. Sauna, N. J. Caplen, H. M. Fales, S. V. Ambudkar, J. N. Weinstein, et al. Selective Toxicity of NSC73306 in MDR1-Positive Cells as a New Strategy to Circumvent Multidrug Resistance in Cancer. Cancer Res., May 1, 2006; 66(9): 4808 - 4815. [Abstract] [Full Text] [PDF]

				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]

				J. V. Skliarenko, S. J. Lunt, M. L. Gordon, A. Vitkin, M. Milosevic, and R. P. Hill Effects of the Vascular Disrupting Agent ZD6126 on Interstitial Fluid Pressure and Cell Survival in Tumors Cancer Res., February 15, 2006; 66(4): 2074 - 2080. [Abstract] [Full Text] [PDF]

				G. J. Kelloff, K. A. Krohn, S. M. Larson, R. Weissleder, D. A. Mankoff, J. M. Hoffman, J. M. Link, K. Z. Guyton, W. C. Eckelman, H. I. Scher, et al. The Progress and Promise of Molecular Imaging Probes in Oncologic Drug Development Clin. Cancer Res., November 15, 2005; 11(22): 7967 - 7985. [Abstract] [Full Text] [PDF]

				R. Clarijs, M. van Dijk, D. J. Ruiter, and R. M. W. de Waal Functional and Morphologic Analysis of the Fluid-Conducting Meshwork in Xenografted Cutaneous and Primary Uveal Melanoma Invest. Ophthalmol. Vis. Sci., September 1, 2005; 46(9): 3013 - 3020. [Abstract] [Full Text] [PDF]

				M. F. Flessner, J. Choi, K. Credit, R. Deverkadra, and K. Henderson Resistance of Tumor Interstitial Pressure to the Penetration of Intraperitoneally Delivered Antibodies into Metastatic Ovarian Tumors Clin. Cancer Res., April 15, 2005; 11(8): 3117 - 3125. [Abstract] [Full Text] [PDF]

				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]

				Q. G. de Lussanet, S. Langereis, R. G. H. Beets-Tan, M. H. P. van Genderen, A. W. Griffioen, J. M. A. van Engelshoven, and W. H. Backes Dynamic Contrast-enhanced MR Imaging Kinetic Parameters and Molecular Weight of Dendritic Contrast Agents in Tumor Angiogenesis in Mice Radiology, April 1, 2005; 235(1): 65 - 72. [Abstract] [Full Text] [PDF]

				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]

				N Nathoo, A Chahlavi, G H Barnett, and S A Toms Pathobiology of brain metastases J. Clin. Pathol., March 1, 2005; 58(3): 237 - 242. [Abstract] [Full Text] [PDF]

				M. F. Flessner, J. Choi, Z. He, and K. Credit Physiological characterization of human ovarian cancer cells in a rat model of intraperitoneal antineoplastic therapy J Appl Physiol, October 1, 2004; 97(4): 1518 - 1526. [Abstract] [Full Text] [PDF]

				L. Eikenes, O. S. Bruland, C. Brekken, and C. d. L. Davies Collagenase Increases the Transcapillary Pressure Gradient and Improves the Uptake and Distribution of Monoclonal Antibodies in Human Osteosarcoma Xenografts Cancer Res., July 15, 2004; 64(14): 4768 - 4773. [Abstract] [Full Text] [PDF]

				M. Dadiani, R. Margalit, N. Sela, and H. Degani High-Resolution Magnetic Resonance Imaging of Disparities in the Transcapillary Transfer Rates in Orthotopically Inoculated Invasive Breast Tumors Cancer Res., May 1, 2004; 64(9): 3155 - 3161. [Abstract] [Full Text] [PDF]

				M. Vavra, M. J. Ali, E. W.-Y. Kang, Y. Navalitloha, A. Ebert, C. V. Allen, and D. R. Groothuis Comparative pharmacokinetics of 14C-sucrose in RG-2 rat gliomas after intravenous and convection-enhanced delivery Neuro-oncol, April 1, 2004; 6(2): 104 - 112. [Abstract] [PDF]

				C. d. L. Davies, L. M. Lundstrom, J. Frengen, L. Eikenes, O. S. Bruland, O. Kaalhus, M. H. B. Hjelstuen, and C. Brekken Radiation Improves the Distribution and Uptake of Liposomal Doxorubicin (Caelyx) in Human Osteosarcoma Xenografts Cancer Res., January 15, 2004; 64(2): 547 - 553. [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]

				P. D. Davis, G. J. Dougherty, D. C. Blakey, S. M. Galbraith, G. M. Tozer, A. L. Holder, M. A. Naylor, J. Nolan, M. R. L. Stratford, D. J. Chaplin, et al. ZD6126: A Novel Vascular-targeting Agent That Causes Selective Destruction of Tumor Vasculature Cancer Res., December 15, 2002; 62(24): 7247 - 7253. [Abstract] [Full Text] [PDF]

				R. Clarijs, I. Otte-Holler, D. J. Ruiter, and R. M. W. de Waal Presence of a Fluid-Conducting Meshwork in Xenografted Cutaneous and Primary Human Uveal Melanoma Invest. Ophthalmol. Vis. Sci., April 1, 2002; 43(4): 912 - 918. [Abstract] [Full Text] [PDF]

				E. K. Rofstad, S. H. Tunheim, B. Mathiesen, B. A. Graff, E. F. Halsor, K. Nilsen, and K. Galappathi Pulmonary and Lymph Node Metastasis Is Associated with Primary Tumor Interstitial Fluid Pressure in Human Melanoma Xenografts Cancer Res., February 1, 2002; 62(3): 661 - 664. [Abstract] [Full Text] [PDF]

				B. S. Kuszyk, F. M. Corl, F. N. Franano, D. A. Bluemke, L. V. Hofmann, B. J. Fortman, and E. K. Fishman Tumor Transport Physiology: Implications for Imaging and Imaging-Guided Therapy Am. J. Roentgenol., October 1, 2001; 177(4): 747 - 753. [Full Text] [PDF]

				T. Karpanen and K. Alitalo Lymphatic Vessels as Targets of Tumor Therapy? J. Exp. Med., September 17, 2001; 194(6): f37 - f42. [Full Text] [PDF]

				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., September 1, 2001; 61(17): 6413 - 6422. [Abstract] [Full Text] [PDF]

				A. de Vries, J. Griebel, C. Kremser, W. Judmaier, T. Gneiting, P. Debbage, T. Kremser, K.-P. Pfeiffer, W. Buchberger, and P. Lukas Monitoring of Tumor Microcirculation during Fractionated Radiation Therapy in Patients with Rectal Carcinoma: Preliminary Results and Implications for Therapy Radiology, November 1, 2000; 217(2): 385 - 391. [Abstract] [Full Text]

				M. Stohrer, Y. Boucher, M. Stangassinger, and R. K. Jain Oncotic Pressure in Solid Tumors Is Elevated Cancer Res., August 1, 2000; 60(15): 4251 - 4255. [Abstract] [Full Text]

				Y. S. Lew, S. L. Brown, R. J. Griffin, C. W. Song, and J. H. Kim Arsenic Trioxide Causes Selective Necrosis in Solid Murine Tumors by Vascular Shutdown Cancer Res., December 1, 1999; 59(24): 6033 - 6037. [Abstract] [Full Text] [PDF]

				G. M. Tozer, V. E. Prise, J. Wilson, R. J. Locke, B. Vojnovic, M. R. L. Stratford, M. F. Dennis, and D. J. Chaplin Combretastatin A-4 Phosphate as a Tumor Vascular-Targeting Agent: Early Effects in Tumors and Normal Tissues Cancer Res., April 1, 1999; 59(7): 1626 - 1634. [Abstract] [Full Text] [PDF]

				P. A. Netti, L. M. Hamberg, J. W. Babich, D. Kierstead, W. Graham, G. J. Hunter, G. L. Wolf, A. Fischman, Y. Boucher, and R. K. Jain Enhancement of fluid filtration across tumor vessels: Implication for delivery of macromolecules PNAS, March 16, 1999; 96(6): 3137 - 3142. [Abstract] [Full Text] [PDF]

				A. Pluen, Y. Boucher, S. Ramanujan, T. D. McKee, T. Gohongi, E. di Tomaso, E. B. Brown, Y. Izumi, R. B. Campbell, D. A. Berk, et al. Role of tumor-host interactions in interstitial diffusion of macromolecules: Cranial vs. subcutaneous tumors PNAS, April 10, 2001; 98(8): 4628 - 4633. [Abstract] [Full Text] [PDF]