title: Enhanced expression of gamma-glutamylcysteine synthetase and glutathione S-transferase genes in cisplatin-resistant bladder cancer cells with multidrug resistance phenotype.
abstract: OBJECTIVE
  To elucidate the mechanisms of cisplatin resistance in human bladder cancer.
  
  
  METHODS
  After continuous exposure of KK47 cells to cisplatin, two resistant sublines, KK47/DDP10 and KK47/DDP20 were established. The glutathione content, glutathione S-transferase activity, and intracellular platinum concentration were measured while the expression of various drug resistance-related genes was examined.
  
  
  RESULTS
  KK47/DDP10 and KK47/DDP20 were respectively 9.3- and 18.7-fold more resistant to cisplatin than KK47, and also showed multidrug resistance. Decreased intracellular drug accumulation, increased glutathione content, elevated glutathione S-transferase activity, and an overexpression of gamma-glutamylcysteine synthetase and glutathione S-transferase pi genes were observed in the resistant sublines.
  
  
  CONCLUSIONS
  Multiple mechanisms, including decreased drug accumulation, increased intracellular glutathione and glutathione S-transferase pi, may contribute to the acquisition of cisplatin resistance in human bladder cancer.
authors.affiliation: Department of Urology and Biochemistry, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kotoh
authors.forename: S
authors.initials: S
authors.lastname: Naito
authors.forename: A
authors.initials: A
authors.lastname: Yokomizo
authors.forename: K
authors.initials: K
authors.lastname: Kohno
authors.forename: M
authors.initials: M
authors.lastname: Kuwano
authors.forename: J
authors.initials: J
authors.lastname: Kumazawa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D019450:Genes, MDR / Q000235:genetics*; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis / Q000235:genetics*; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D005982:Glutathione Transferase; D005721:Glutamate-Cysteine Ligase; D002945:Cisplatin