This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Choi, J. Articles by Flessner, M. F. Search for Related Content PubMed PubMed Citation Articles by Choi, J. Articles by Flessner, M. F.

Intraperitoneal Immunotherapy for Metastatic Ovarian Carcinoma: Resistance of Intratumoral Collagen to Antibody Penetration

Authors' Affiliations: ¹ Department of Medicine and ² Pathology, University of Mississippi Medical Center, Jackson, Mississippi and ³ Department of Biomedicine, University of Bergen, Bergen, Norway

Requests for reprints: Michael F. Flessner, Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505. Phone: 601-984-5670; Fax: 601-984-5765; E-mail: mflessner{at}medicine.umsmed.edu.

Purpose: Convective transport of macromolecules from the peritoneal cavity into tumor is determined by its hydraulic permeability and the pressure gradient. Previous studies showed that establishing a pressure gradient into the tumor failed to result in significant penetration. This study addresses the hypothesis that the extracellular matrix is the major resistance to the penetration of an i.p. injected antibody.

Experimental Design: Human ovarian tumors (SKOV-3 and OVCAR-3) were established in the abdominal wall of athymic rats. After anesthesia, the tumor serosal surface was treated for 2 hours with Krebs solution (control), collagenase (37.5 unit/mL), or hyaluronidase (10 unit/mL) followed by 3 hours of convective delivery of radiolabeled IgG. Transport of antibody into the tumor was measured with quantitative autoradiography along with the tumor interstitial pressure, concentration of collagen and hyaluronic acid, and IgG volume of distribution.

Results: Antibody was excluded from 42% to 53% of tumor extracellular volume. Exposure of tumors to hyaluronidase did not enhance IgG transport despite removal of 90% of the hyaluronan from the exposed tumor. In contrast, collagenase reduced collagen content, lowered tumor interstitial pressure, and markedly enhanced antibody penetration.

Conclusions: Reduction of collagen, but not hyaluronan, in the matrix of ovarian xenografts enhanced the transport of i.p. injected antibody. Although high interstitial pressure is a deterrent to convective transport of macromolecules into the tumor parenchyma, the structure of the interstitial matrix provides an inherent resistance, which must be overcome before effective delivery of an antibody.

This article has been cited by other articles:

				J. Henshaw, B. Mossop, and F. Yuan Relaxin treatment of solid tumors: effects on electric field-mediated gene delivery Mol. Cancer Ther., August 1, 2008; 7(8): 2566 - 2573. [Abstract] [Full Text] [PDF]

				J. H.E. Baker, K. E. Lindquist, L. A. Huxham, A. H. Kyle, J. T. Sy, and A. I. Minchinton Direct Visualization of Heterogeneous Extravascular Distribution of Trastuzumab in Human Epidermal Growth Factor Receptor Type 2 Overexpressing Xenografts Clin. Cancer Res., April 1, 2008; 14(7): 2171 - 2179. [Abstract] [Full Text] [PDF]

				P. Sabbatini and K. Odunsi Immunologic Approaches to Ovarian Cancer Treatment J. Clin. Oncol., July 10, 2007; 25(20): 2884 - 2893. [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]