title: Cucurbit [7] uril encapsulated cisplatin overcomes resistance to cisplatin induced by Rab25 overexpression in an intraperitoneal ovarian cancer model.
abstract: BACKGROUND
  Ovarian cancer is the most fatal of gynaecological malignancies, usually detected at a late stage with intraperitoneal dissemination. Appropriate preclinical models are needed that recapitulate both the histopathological and molecular features of human ovarian cancer for drug-efficacy analysis.
  
  
  METHODS
  Longitudinal studies comparing cisplatin performance either alone or in a novel cisplatin-based delivery-system, cucurbit[7]uril-encapsulated cisplatin (cisplatin@CB[7]) were performed on subcutaneous (s.c.) and intraperitoneal (i.p.) xenografts using the human ovarian cancer cell line A2780 stably expressing the small GTPase Rab25, which allows A2780 intraperitoneal growth; and luciferase, to allow tumour load measurement by non-invasive bioluminescent imaging.
  
  
  RESULTS
  Rab25 expression induced cisplatin resistance compared to the parental cell line as assessed by the MTT assay in vitro. These findings did not translate in vivo, where cisplatin resistance was determined by the microenvironment. Subcutaneous xenografts of either parental A2780 or cisplatin-resistant Rab25-expressing A2780 cells presented similar responses to cisplatin treatment. In contrast, increased cisplatin resistance was only detected in i.p. tumours. Treatment of the cisplatin-resistant i.p. model with the novel cisplatin@CB[7] delivery system resulted in a substantial reduction of i.p. tumour load and increased necrosis.
  
  
  CONCLUSIONS
  Poor clinical performance of novel chemotherapeutics might reflect inappropriate preclinical models. Here we present an ovarian i.p. model that recapitulates the histopathological and chemoresistant features of the clinical disease. In addition, we demonstrate that the novel cisplatin-delivery system, cisplatin@CB[7] may have utility in the treatment of drug-resistant ovarian human cancers.
authors.affiliation: Institute of Cancer Sciences, Wolfson Wohl Translational Cancer Research Centre, University of Glasgow, Bearsden, Garscube Estate, Glasgow, G61 1QH, , Scotland, UK. n.gomez-roman@beatson.gla.ac.uk.
authors.forename: Natividad
authors.initials: N
authors.lastname: Gomez-Roman
authors.affiliation: Institute of Cancer Sciences, Wolfson Wohl Translational Cancer Research Centre, University of Glasgow, Bearsden, Garscube Estate, Glasgow, G61 1QH, , Scotland, UK. Fiona.mcgregor@glasgow.ac.uk.
authors.forename: Fiona
authors.initials: F
authors.lastname: McGregor
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia. nial.wheate@sydney.edu.au.
authors.forename: Nial J
authors.initials: NJ
authors.lastname: Wheate
authors.affiliation: Institute of Cancer Sciences, Wolfson Wohl Translational Cancer Research Centre, University of Glasgow, Bearsden, Garscube Estate, Glasgow, G61 1QH, , Scotland, UK. jane.plumb@glasgow.ac.uk.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Plumb
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002214:Capsules; D002277:Carcinoma / Q000188:drug therapy; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D064593:Heterografts / Q000378:metabolism; D007267:Injections; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010534:Peritoneal Neoplasms / Q000188:drug therapy; D011506:Proteins / Q000378:metabolism*; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002214:Capsules; C426009:LAMTOR2 protein, mouse; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin