title: Altered expression of gamma-glutamylcysteine synthetase, metallothionein and topoisomerase I or II during acquisition of drug resistance to cisplatin in human ovarian cancer cells.
abstract: This study was designed to elucidate the mechanisms of cisplatin (CDDP) resistance using two human ovarian cancer cell lines, KF and TYK, and two CDDP-resistant lines, KFr and TYK/R, derived from the former lines. KFr and TYK/R showed about 3-fold higher resistance to the cytotoxic effects of CDDP than their parental lines. They also showed a significant increase in sensitivity to not only etoposide, but also (+)-(4S)-4, 11-diethyl-4-hydroxy-9-[(4-piperidino -piperidino)carbonyloxy]-1H -pyrano[3',4':6,7]inodolizino[1,2-b]quinoline-3,14(4H, 12H)-dione hydrochloride trihydrate (CPT-11). Cellular CDDP accumulation levels in KFr and TYK/R were decreased from those of the parental cells. By contrast, the cellular glutathione (GSH) content in KFr cells was 1.7-fold higher than that in KF, whereas TYK/R cells had a 40% lower content than TYK cells. Cellular mRNA levels of drug-resistance-related genes, such as DNA topoisomerase (topo) I and topo II, glutathione S-transferase-pi (GST-pi), gamma-glutamylcysteine synthetase (gamma-GCS), and metallothionein (hMT) genes, were compared between drug-sensitive KF or TYK and KFr or TYK/R. KFr cells had 8.5- and 24.7-fold higher mRNA levels of gamma-GCS and topo II genes than KF cells while KFr had only a slight increase in GST-pi mRNA level as compared with KF. By contrast, TYK/R cells had 2.9- and 1.7-fold higher hMT and topo I mRNA levels than TYK cells. Acquisition of CDDP resistance in human ovarian cancer cells thus appeared to be related mainly to expression of gamma-GCS, topo II and hMT genes, and partly to that of topo I and GST-pi genes, in addition to a decrease in CDDP accumulation.
authors.affiliation: Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa.
authors.forename: Y
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: J
authors.initials: J
authors.lastname: Hirata
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: K
authors.initials: K
authors.lastname: Ishii
authors.forename: T
authors.initials: T
authors.lastname: Kita
authors.forename: K
authors.initials: K
authors.lastname: Kudoh
authors.forename: T
authors.initials: T
authors.lastname: Tode
authors.forename: I
authors.initials: I
authors.lastname: Nagata
authors.forename: K
authors.initials: K
authors.lastname: Taniguchi
authors.forename: M
authors.initials: M
authors.lastname: Kuwano
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism*; D002945:Cisplatin / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism*; D006801:Humans; D008668:Metallothionein / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D008668:Metallothionein; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D005721:Glutamate-Cysteine Ligase; D002945:Cisplatin