title: Novel in vitro model barriers for evaluation of the permeability of antitumor compounds, thioxanthones.
abstract: Anticancer drugs have to cross many layers of cells and the extracellular matrix to reach the tumor cells and elicit their pharmacological action. The three dimensional structure (micro-environment) of tumors poses a penetration barrier to antitumor drugs resulting in poor response. Two in vitro model barriers representing the extracellular matrix and multilayered structure of tumors were used in this study to evaluate the permeability of four structurally related antitumor compounds, thioxanthones. Matrigel was used to represent the tumor extracellular matrix and multilayered Caco-2 cells were used to represent the multilayered confluence of solid tumor. The in vitro permeability characteristics of the thioxanthones across the model barriers were correlated to their in vivo distribution. The apparent permeability coefficients of thioxanthone analogs are in the range of 2.9 x 10(-6) to 11.8 x 10(-6) cm/s across matrigel and 12.6 x 10(-6) to 24.5 x 10(-6) cm/s across Caco-2 multilayers. This high in vitro permeability of thioxanthones across the model barriers suggested their good tissue distribution in vivo. Therefore, the use of in vitro model barriers was found to predict in vivo tissue distribution for thioxanthones.
authors.affiliation: Department of Pharmaceutics & Medicinal Chemistry, TJ Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA 95211, USA.
authors.forename: Venugopal
authors.initials: V
authors.lastname: Marasanapalle
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.forename: Lisa
authors.initials: L
authors.lastname: Polin
authors.forename: Bhaskara R
authors.initials: BR
authors.lastname: Jasti
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D018938:Caco-2 Cells / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D010539:Permeability; D011509:Proteoglycans / Q000378:metabolism; D013892:Thioxanthenes / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D044004:Xanthones / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D013892:Thioxanthenes; D044004:Xanthones; C402303:SR 271425; C059485:matrigel; D003094:Collagen; C484911:thioxanthone