title: ABCG2 mediates differential resistance to SN-38 (7-ethyl-10-hydroxycamptothecin) and homocamptothecins.
abstract: One activity potentially limiting the efficacy of camptothecin anticancer agents is their cellular efflux by the ATP-binding cassette half-transporter, ABCG2. Homocamptothecins are novel anticancer drugs that inhibit topoisomerase 1 with a greater potency than camptothecins. Homocamptothecins differ from camptothecins by their E-ring, which is seven-membered instead of the six-membered ring of camptothecins. We report herein that, like camptothecins, homocamptothecin and its difluoro derivative BN80915 are substrates for ABCG2. However, the resistance of three selected cell lines overexpressing wild-type or mutant ABCG2 to homocamptothecin or BN80915 was less than resistance to SN-38 (7-ethyl-10-hydroxycamptothecin), indicating that both the seven-membered E-ring present in homocamptothecin and the A- and B-ring modifications present in SN-38 are involved in substrate recognition by ABCG2. HEK-293 cells transfected with vectors encoding wild-type or mutant ABCG2 were found to be less resistant to both homocamptothecins than to SN-38. However, transfectants overexpressing mutant ABCG2 had relative resistance values for homocamptothecin and BN80915 4- to 14-fold higher than cells expressing wild-type ABCG2, suggesting that the gain of function resulting from mutation at amino acid 482, although not affecting SN-38, extends to the homocamptothecins. Resistance was reversed by the ABCG2 inhibitor fumitremorgin C. BN80915 was 17-fold more potent than SN-38 in wild-type ABCG2-transfected cells, suggesting that BN80915 has the potential to overcome ABCG2-related resistance to SN-38, the active metabolite of CPT-11 (irinotecan).
authors.affiliation: Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bldg. 10 Rm. 12C103, Bethesda, MD 20892, USA. sebates@helix.nih.gov
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.forename: Wilma Y
authors.initials: WY
authors.lastname: Medina-Pérez
authors.forename: Glenda
authors.initials: G
authors.lastname: Kohlhagen
authors.forename: Smitha
authors.initials: S
authors.lastname: Antony
authors.forename: Tim
authors.initials: T
authors.lastname: Nadjem
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000077146:Irinotecan; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D059004:Topoisomerase I Inhibitors
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; C120029:homocamptothecin; D002166:Camptothecin