title: Novel camptothecin analogues that circumvent ABCG2-associated drug resistance in human tumor cells.
abstract: Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin; CPT-11) is a widely used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I); however, overexpression of ABCG2 (BCRP/MXR/ABCP) can confer cancer cell resistance to SN-38, the active form of CPT-11. We have recently demonstrated that plasma membrane vesicles prepared from ABCG2-overexpressing PC-6/SN2-5H cells transported SN-38 and its glucuronide conjugate in an ATP-dependent manner (Nakatomi et al., Biochem Biophys Res Commun 2001;288:827-32). In the present study, we have characterized a total of 14 new camptothecin (CPT) analogues with respect to both the inhibition of Topo I and the substrate specificity of ABCG2. All of the tested CPT analogues, which have different substitutions at positions 10 and 11, strongly inhibited the Topo I activity in a cell-free system, as did SN-38. Their antitumor activities in the SN-38-resistant PC-6/SN2-5H2 cell line greatly varied, however, being correlated with intracellular accumulation levels. We have examined ATP-dependent transport of those CPT analogues by using plasma membrane vesicles prepared from both PC-6/SN2-5H2 cells and ABCG2-transfected HEK-293 cells. Based on the substrate specificity of ABCG2 thus evaluated, it is strongly suggested that CPT analogues with high polarity are good substrates for ABCG2 and are therefore effectively extruded from cancer cells. In this context, to circumvent ABCG2-associated drug resistance, low-polarity CPT analogues are considered to be potent lead compounds. 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 Drug Metabolism and Disposition, Meiji Pharmaceutical University, Noshio 2-522-1, Kiyose, Tokyo 204-8588, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Yoshikawa
authors.forename: Yoji
authors.initials: Y
authors.lastname: Ikegami
authors.forename: Shinya
authors.initials: S
authors.lastname: Hayasaka
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Ishii
authors.forename: Akiko
authors.initials: A
authors.lastname: Ito
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sano
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tadayasu
authors.initials: T
authors.lastname: Togawa
authors.forename: Hisahiro
authors.initials: H
authors.lastname: Yoshida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Soda
authors.forename: Mikio
authors.initials: M
authors.lastname: Oka
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
authors.forename: Seigo
authors.initials: S
authors.lastname: Sawada
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Shinzo
authors.initials: S
authors.lastname: Tanabe
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000633:toxicity; D001692:Biological Transport; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D018288:Carcinoma, Small Cell; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D003001:Cloning, Molecular; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms; D009363:Neoplasm Proteins / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D000255:Adenosine Triphosphate; D002166:Camptothecin