This Article Full Text 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 Eikenes, L. Articles by Davies, C. d. L. Search for Related Content PubMed PubMed Citation Articles by Eikenes, L. Articles by Davies, C. d. L.

Collagenase Increases the Transcapillary Pressure Gradient and Improves the Uptake and Distribution of Monoclonal Antibodies in Human Osteosarcoma Xenografts

¹ Department of Physics and ² Department of Circulation and Medical Imaging, The Norwegian University of Science and Technology, Trondheim, Norway; and ³ Department of Radiotherapy and Oncology, The Norwegian Radium Hospital, Oslo, Norway

Cancer therapy based on tumor-selective macromolecules may fail due to the elevated interstitial fluid pressure (IFP) that reduces the transvascular and interstitial convection in solid tumors. Modulation of the tumor extracellular matrix (ECM) may reduce IFP and enhance transvascular filtration and interstitial transport of macromolecules. We therefore measured the effect of the ECM-degrading enzyme collagenase on IFP and microvascular pressure (MVP) in human osteosarcoma xenografts using the wick-in-needle and micropipette methods, respectively. The tumor uptake and distribution of a systemically administered osteosarcoma-associated monoclonal antibody (TP-3) after i.v. injection of collagenase were analyzed using confocal laser scanning microscopy. Collagenase (0.1%) reduced both IFP (45%) and MVP (60%), but the kinetics of the recoveries differed, because MVP had recovered by the time IFP reached its minimum level. Thus, collagenase increased the transcapillary pressure gradient, inducing a 2-fold increase in the tumor uptake and improving the distribution of the monoclonal antibody, which was localized further into the tumor. To study the mechanism of the reduction in MVP, mean arterial blood pressure was measured and found not to be affected by the collagenase treatment. The reduction in MVP was rather due to reduced vascular resistance because microvascular-associated collagen was totally or partially disintegrated. Although collagenase may favor metastasis and thus not be clinically relevant, this study shows proof of principle that degradation of the ECM leads to a favorable change in the transvascular pressure gradient, thereby increasing antibody penetration and binding to tumor cells.

This article has been cited by other articles:

				T. P.F. Gade, I. M. Buchanan, M. W. Motley, Y. Mazaheri, W. M. Spees, and J. A. Koutcher Imaging Intratumoral Convection: Pressure-Dependent Enhancement in Chemotherapeutic Delivery to Solid Tumors Clin. Cancer Res., January 1, 2009; 15(1): 247 - 255. [Abstract] [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]

				D. Lu, M. G. Wientjes, Z. Lu, and J. L.-S. Au Tumor Priming Enhances Delivery and Efficacy of Nanomedicines J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 80 - 88. [Abstract] [Full Text] [PDF]

				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]

				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. Choi, K. Credit, K. Henderson, R. Deverkadra, Z. He, H. Wiig, H. Vanpelt, and M. F. Flessner Intraperitoneal immunotherapy for metastatic ovarian carcinoma: resistance of intratumoral collagen to antibody penetration. Clin. Cancer Res., March 15, 2006; 12(6): 1906 - 1912. [Abstract] [Full Text] [PDF]

				R. Cairns, I. Papandreou, and N. Denko Overcoming Physiologic Barriers to Cancer Treatment by Molecularly Targeting the Tumor Microenvironment Mol. Cancer Res., February 1, 2006; 4(2): 61 - 70. [Abstract] [Full Text] [PDF]

				H. Wiig, C. C. Gyenge, and O. Tenstad The interstitial distribution of macromolecules in rat tumours is influenced by the negatively charged matrix components J. Physiol., September 1, 2005; 567(2): 557 - 567. [Abstract] [Full Text] [PDF]

				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]