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1 Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA; Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA
* To whom correspondence should be addressed. E-mail: mflessner{at}medicine.umsmed.edu.
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. CD-31 immunohistochemistry revealed unique patterns of angiogenesis, with a tissue-averaged vascular volume of ~0.01 ml/g for each tumor. The extracellular volume (0.54±0.11 ml/g, n=5, SKOV3; 0.61±0.03, n=5, OVCAR3) was over twice that of the adjacent normal muscle (0.22±0.06 ml/g, n=5). Iv-injected 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 [14C]mannitol or 125I-immunoglobulin G (IgG; trastuzumab) was performed to determine transport of small and large molecules. With ip pressure = 0-6 mmHg, both mannitol and IgG 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.
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