title: Reversal of drug resistance using hammerhead ribozymes against multidrug resistance-associated protein and multidrug resistance 1 gene.
abstract: We examined the effects of suppressing multidrug resistance-associated protein (MRP) and multidrug resistance 1 (MDR1) gene expression in HCT-8DDP human colon cancer cell lines, which showed both cisplatin and multidrug resistance. Hammerhead ribozymes, designed to cleave MRP mRNA (anti-MRP Rz) and MDR1 mRNA (anti-MDR1 Rz), were transfected into the HCT-8DDP cells. Drug sensitivity was estimated by MTT assay in vitro. The HCT-8DDP/anti-MRP Rz cells were more sensitive to doxorubicin (DOX) and etoposide (VP-16) by 2.5- and 4.1-fold, respectively, compared with HCT-8DDP cells. The HCT-8DDP/anti-MDR Rz cells were more sensitive to DOX and VP-16 by 2.3- and 3.8-fold, respectively. The anti-MRP Rz and anti-MDR1 Rz significantly down-regulated resistance to DOX and VP-16, while anti-MRP Rz and anti-MDR1 Rz did not affect resistance to cisplatin, methotrexate and 5-fluorouracil. The hammerhead ribozyme-mediated specific suppression of MRP or MDR1 was sufficient to reverse multidrug resistance in the human colon cancer cell line.
authors.affiliation: Department of Pathology, Tokai University School of Medicine, Bohseidai, Isehara-shi, Kanagawa 259-1193, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Nagata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kijima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hatanaka
authors.forename: Satomi
authors.initials: S
authors.lastname: Asai
authors.forename: Hayato
authors.initials: H
authors.lastname: Miyachi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Abe
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Masato
authors.initials: M
authors.lastname: Nakamura
authors.forename: Norihito
authors.initials: N
authors.lastname: Watanabe
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mine
authors.forename: Takahito
authors.initials: T
authors.lastname: Kondo
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Scanlon
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Ueyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D019450:Genes, MDR; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D016337:RNA, Catalytic / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016337:RNA, Catalytic