title: The activity of trabectedin as a single agent or in combination with everolimus for clear cell carcinoma of the ovary.
abstract: OBJECTIVE
  The objective of this study was to evaluate the antitumor efficacy of trabectedin in clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histologic subtype.
  
  
  METHODS
  Using 6 human ovarian cancer cell lines (3 CCC and 3 serous adenocarcinomas), the antitumor effects of trabectedin were examined in vitro, and we compared its activity according to histology. We next examined the antitumor activity of trabectedin in both cisplatin-resistant and paclitaxel-resistant CCC cells in vitro. Then, the in vivo effects of trabectedin were evaluated using mice inoculated with CCC cell lines. Using 2 pairs of trabectedin-sensitive parental and trabectedin-resistant CCC sublines, we investigated the role of mTOR in the mechanism of acquired resistance to trabectedin. Finally, we determined the effect of mTOR inhibition by everolimus on the antitumor efficacy of trabectedin in vitro and in vivo.
  
  
  RESULTS
  Trabectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that trabectedin significantly inhibits tumor growth. Greater activation of mTOR was observed in trabectedin-resistant CCC cells than in their respective parental cells. The continuous inhibition of mTOR significantly enhanced the therapeutic efficacy of trabectedin and prevented CCC cells from acquiring resistance to trabectedin.
  
  
  CONCLUSIONS
  Trabectedin is a promising agent for CCC as a first-line chemotherapy and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel. Moreover, trabectedin combined with everolimus may be more efficacious for the management of CCC.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan. smabuchi@gyne.med.osaka-u.ac.jp
authors.forename: Seiji
authors.initials: S
authors.lastname: Mabuchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hisamatsu
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kawase
authors.forename: Masami
authors.initials: M
authors.lastname: Hayashi
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sawada
authors.forename: Kazuya
authors.initials: K
authors.lastname: Mimura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takahashi
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kurachi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kimura
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D000068338:Everolimus; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D000068338:Everolimus; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000077606:Trabectedin; D020123:Sirolimus