title: Transport mechanism-based drug molecular design: novel camptothecin analogues to circumvent ABCG2-associated drug resistance of human tumor cells.
abstract: Acquired and intrinsic drug resistance in cancer is the major obstacle to long-term, sustained patient response to chemotherapy. Irinotecan (CPT-11) is a widely-used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I). However, overexpression of ABCG2 (BCRP/MXR/ABCP) reportedly confers cancer cells resistance to SN-38, the active form of CPT-11. To circumvent the ABCG2-associated drug resistance, we have synthesized and characterized a total of fourteen new camptothecin (CPT) analogues with respect to both the inhibition of Topo I and the substrate specificity of ABCG2. While the lactone E ring is a prerequisite for anticancer activity, modifications of the A or B rings do not significantly affect Topo I inhibition activity. In this context, we have synthesized new CPT analogues with different substitutions at positions 10 or 11 of the A ring. All of the tested CPT analogues strongly inhibited the Topo I activity in a cell-free system. Accordingly, we have examined ATP-dependent transport of those CPT analogues by using plasma membrane vesicles prepared from ABCG2-overexpressing cells. Based on the substrate specificity of ABCG2 thus evaluated, it is strongly suggested that CPT analogues with a hydroxyl group at position 10 or 11 of the A ring are good substrates for ABCG2 and therefore effectively extruded from cancer cells. Thus, hydrogen bond formation is considered to be involved in substrate recognition and/or transport processes of ABCG2. The present study provides a practical approach to discover new CPT-based drugs for the chemotherapy of drug-resistant human cancer.
authors.affiliation: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B-60 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan. tishikaw@bio.titech.ac.jp
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Yoji
authors.initials: Y
authors.lastname: Ikegami
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Seigo
authors.initials: S
authors.lastname: Sawada
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D059004:Topoisomerase I Inhibitors
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin