title: Image-based evaluations of distribution and cytotoxicity of Irinotecan (CPT-11) in a multi-compartment micro-cell coculture device.
abstract: We recently developed a polydimethylsiloxane (PDMS)-based three-compartment microfluidic cocultivation device enabling real-time interactions of different cell populations as an advanced physiologically-relevant cell-based assay. This device had valves and small magnetic stirrer-based internal pumps for easy and flexible perfusion operations. In this study, we applied this device for the evaluation of Irinotecan (CPT-11) toxicity to the lung, because it is detoxified by the liver and accumulated in the fat in humans. We successfully cultured representative three different tissue model cells in each compartment under the individual culture conditions and also in entire perfusion. Growth inhibition of rat lung epithelial cell line L-2, was measured when administered with 50 μM CPT-11 under various cocultivation conditions with respect to the presences and absence of primary rat hepatocytes (liver tissue model) and adipocyte-like cells (fat tissue model) induced from a mouse fibroblast cell line, 3T3-L1. Although CPT-11 showed moderate toxicity to the pure culture of L-2 cells in the device after 72 h of perfusion culture, this was lowered mainly in the presence of the liver tissue. Inhibition of the L-2 cell growth agreed with the area under curve (AUC) values obtained from fluorescent image-based analyses in each compartment. These results demonstrate that developed simple and flexible microfluidic cocultivation device, with appropriate image-based analyses, can be used in evaluating toxicokinetic behaviors of drug candidates in systemic levels.
authors.affiliation: Institute of Industrial Science (IIS), University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
authors.forename: Hidenari
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Institute of Industrial Science (IIS), University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Institute of Industrial Science (IIS), University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Institute of Industrial Science (IIS), University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan. Electronic address: sakaiyas@iis.u-tokyo.ac.jp.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sakai
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000502:physiology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques / Q000295:instrumentation; D004129:Dimethylpolysiloxanes / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor / Q000295:instrumentation; D022781:Hepatocytes / Q000502:physiology; D000077146:Irinotecan; D051379:Mice; D046210:Microfluidic Analytical Techniques; D008856:Microscopy, Fluorescence; D051381:Rats
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004129:Dimethylpolysiloxanes; C013830:baysilon; D000077146:Irinotecan; D002166:Camptothecin
keywords: Coculture; Distribution; Irinotecan; Microdevice; Multi-compartment; Systemic toxicity