Innovative Methodology Physiological characterization of human ovarian cancer cells in a rat model of intraperitoneal antineoplastic therapy

Flessner, Michael F., Jaehwa Choi, Zhi He, and Kimberly Credit. Physiological characterization of human ovarian cancer cells in a rat model of intraperitoneal antineoplastic therapy. J Appl Physiol 97: 1518 –1526, 2004. First published June 4, 2004; 10.1152/ japplphysiol.00305.2004.—Destruction of cancer cells by therapies directed against new molecular targets requires their effective delivery to the tumor. To study diffusion and convection of intraperitoneal (ip) therapy to ip tumors, we established a new athymic rat (RNU) model with ovarian tumor cells (SKOV3 and OVCAR3) implanted in the abdominal wall. The model simulates metastatic tumor and facilitates the measurement of physiological parameters that govern transport forces. CD31 immunohistochemistry revealed unique patterns of angiogenesis, with a tissue-averaged vascular volume of 0.01 ml/g for each tumor. The extracellular volume (SKOV3: 0.54 0.11 ml/g, n 5; OVCAR3: 0.61 0.03, n 5) was over twice that of the adjacent normal muscle (0.22 0.06 ml/g, n 5). Intravenousinjected antibody tumor clearance was two to three times that of muscle. Interstitial pressures were higher than normal tissue with a median of 10–15 mmHg. Quantitative autoradiography of frozen tissue slices from rats exposed to ip solutions containing [C]mannitol or I-immunoglobulin G (trastuzumab) was performed to determine transport of small and large molecules. With ip pressure of 0–6 mmHg, both mannitol and immunoglobulin G displayed steep concentration profiles close to the tumor surface with limited penetration deeper within the tumor tissue; antibody penetration was significantly affected by ip pressure. These results demonstrated effects of molecular size, ip pressure, the limited but highly permeable tumor vasculature, and the expanded interstitium on drug penetration from the peritoneal cavity. In conclusion, we have characterized physical and chemical parameters that determine transport of therapeutic agents in our unique tumor-bearing rat model.