Michael F. Flessner
University of Rochester
The peritoneum forms the thin (< 100 Ám) lining of the abdominal cavity and is made up of a single layer of mesothelial cells overlying several layers of connective tissue. Intraabdominal cancers, such as ovarian or colorectal carcinoma, metastasize from the primary tumor to sites throughout the peritoneum. To treat these micrometastases, large volume (2-3 l) solutions containing monoclonal antibodies (Mabs) which bind specifically to the tumor cells are infused into the cavity and allowed to dwell for hours until absorbed. Our goal in recent years has been to study the diffusive and convective mechanisms of Mab transport from the cavity into the surrounding tissue. Our current conceptual model is equivalent to transport through porous media and incorportates unidirectional diffusion and convection with uniformly distributed sites of lymphatic removal and binding to tissue. The transport coefficients K (tissue hydraulic conductivity), interstitium and solute (fractions of tissue which are available for transport of water and solute, respectively), and Deff (effective diffusivity) are variable and dependent on the mean tissue pressure. In order to determine these coefficients, we utilize an in vivo rat model with large peritoneal volumes to simulate the human treatment. The solutions set up cavity-to-tissue hydrostatic pressure gradients, which provide the driving force for convective transport of the MAbs. Surprisingly, the peritoneum itself does not present a significant barrier to Mab in comparison to the underlying interstitium which surrounds cells and the distributed system of tissue lymphatics which are a major site of Mab removal. We have measured pressure profiles in the anterior abdominal wall of rats and coupled these measurements with quantitative autoradiographic determinations of tracer concentration profiles within the tissue to determine K, interstitium and solute and Deff. With increases of i.p. pressure from 2 to 10 cm H2O, we measured a doubling of the value for interstitium and a fourfold variation in K. Mabs were excluded from 90-95% of the underlying tissue space and undergo processes of binding to specific and nonspecific sites in the tissue. Current work involves measurements of Mab concentration profiles within tissue versus time and i.p. pressure. Model simulations are being compared with these time-dependent profiles in ongoing work to validate and improve the mathematical formulation.