title: Topotecan and doxorubicin combination to treat recurrent ovarian cancer: the influence of drug exposure time and delivery systems to achieve optimum therapeutic activity.
abstract: OBJECTIVE
  To provide proof-of-concept data to support use of Doxil-liposomal topotecan (Topophore C) combinations to treat ovarian cancer.
  
  
  METHODS
  ES-2, OVCAR-3, and SKOV-3 ovarian cancer cell lines were treated with doxorubicin-topotecan combinations by exposing the cells to drugs from 1 to 72 hours. Pharmacokinetic analysis was conducted following administration of liposomal formulations of these drugs alone and in combination. Efficacy assessments were completed in ES-2 and SKOV-3 ovarian cancer models.
  
  
  RESULTS
  On the basis of drug doses capable of achieving 50% reduction in cell viability over 72 hours, doxorubicin-topotecan combinations were additive in SKOV-3 but highly synergistic in ES-2 and OVCAR-3 cells. Favorable drug-drug interactions increased with increased drug exposure time. Topophore C pharmacokinetic remained unaffected when co-administered with Doxil. In the ES-2 model, Doxil at maximum tolerated dose (MTD 7.5 mg/kg) in combination with free topotecan (MTD 15 mg/kg) did not enhance median survival time (MST) over that achieved with topotecan alone. In contrast, MST was increased to 52 days with combination of Topophore C (MTD 2.5 mg/kg) and Doxil (7.5 mg/kg) compared with untreated animals (MST 18 days) or those treated with Topophore C alone (MTD 5 mg/kg, MST 40 days). In the SKOV-3 model, combination treatments showed better therapeutic efficacy than the individual drugs.
  
  
  CONCLUSIONS
  Topotecan-doxorubicin combinations produced additive or synergistic effects which were best achieved when the tumor cells were exposed to drugs over extended time. Doxil-Topophore C combinations are therapeutically superior as judged in two ovarian cancer models. Clin Cancer Res; 19(4); 865-77. ©2012 AACR.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada. npatankar@gmail.com
authors.forename: Nilesh A
authors.initials: NA
authors.lastname: Patankar
authors.forename: Julia
authors.initials: J
authors.lastname: Pritchard
authors.forename: Mariska
authors.initials: M
authors.lastname: van Grinsven
authors.forename: Maryam
authors.initials: M
authors.lastname: Osooly
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008081:Liposomes; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols; D019772:Topotecan / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D008081:Liposomes; D011092:Polyethylene Glycols; D019772:Topotecan; D004317:Doxorubicin