title: Combination drug delivery strategy for the treatment of multidrug resistant ovarian cancer.
abstract: The onset of multidrug resistance (MDR) in ovarian cancer is one of the main causes of treatment failure and low survival rates. Inadequate drug exposure and treatment-free periods due to intermittent chemotherapy select for cancer cells overexpressing drug efflux transporters, resulting in resistant disease. The present study examines the sustained administration of the chemotherapeutic agent docetaxel (DTX) alone and in combination with cepharanthine (CEP), a potent drug efflux transporter inhibitor. DTX and CEP were delivered via the intraperitoneal route in a sustained manner using an injectable polymer-lipid formulation. In vitro, the combination strategy resulted in significantly (p < 0.05) more apoptosis, greater intracellular accumulation of DTX, and lower DTX efflux in ovarian cancer cells showing the MDR phenotype. In vivo, sustained treatment with DTX and CEP showed significantly greater (p < 0.05) tumor inhibition (91 ± 4%) in a murine model of multidrug resistant ovarian cancer compared to sustained DTX treatment (76 ± 6%) and was more than twice as efficacious as intermittent DTX treatment. Overall findings from these studies highlight the impact of sustained delivery of monotherapy and combination therapy in the management of refractory ovarian cancer displaying the MDR phenotype.
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Payam
authors.initials: P
authors.lastname: Zahedi
authors.forename: Raquel
authors.initials: R
authors.lastname: De Souza
authors.forename: Loan
authors.initials: L
authors.lastname: Huynh
authors.forename: Micheline
authors.initials: M
authors.lastname: Piquette-Miller
authors.forename: Christine
authors.initials: C
authors.lastname: Allen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D044182:Benzylisoquinolines / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D043823:Taxoids / Q000627:therapeutic use*; D052117:Benzodioxoles
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D044182:Benzylisoquinolines; D000077143:Docetaxel; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D043823:Taxoids; C513055:ABCB1 protein, human; C421142:ABCC10 protein, human; C006947:cepharanthine; D052117:Benzodioxoles