Intraperitoneal immunotherapy for metastatic ovarian carcinoma: Resistance of intratumoral collagen to antibody penetration.
OBJECTIVE
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.


METHODS
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.
Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, USA.
Jaehwa
J
Choi
Kimberly
K
Credit
Karla
K
Henderson
Ravi
R
Deverkadra
Zhi
Z
He
Helge
H
Wiig
Heather
H
Vanpelt
Michael F
MF
Flessner
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism*; D017364:Collagenases / Q000008:administration & dosage; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000008:administration & dosage; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D007274:Injections, Intraperitoneal; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051381:Rats; D011923:Rats, Nude; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D003094:Collagen; D006821:Hyaluronoglucosaminidase; D017364:Collagenases; D000068878:Trastuzumab