title: In vitro effects on MCF-7 breast cancer cells of signal transduction inhibitor/tamoxifen/eicosapentaenoic acid combinations and their simultaneous delivery across skin.
abstract: OBJECTIVE
  To determine the in vitro effects of simultaneously administered LY29400, PD98059, tamoxifen and eicosapentaenoic acid (EPA) on breast cancer cells, and determine their transcutaneous delivery.
  
  
  METHODS
  Growth assays were performed on MCF-7 cells challenged with IC(50) and permeated concentrations of PD98059, LY294002 and tamoxifen firstly in isolation then combined. Permeation studies were performed using PD98059 and LY294002 (singly or simultaneously) in DMSO then fish oil, with enhancers. Immunocytochemical detection of phospho-MAPK, phospho-Akt, total COX-2 and Ki-67 was performed.
  
  
  RESULTS
  When applied singly, fluxes of PD98059 and LY294002 were 0.09 +/- 0.008 and 0.14 +/- 0.045 microg cm(-2) h(-1), respectively; applied simultaneously, 0.18 +/- 0.045 and 0.49 +/- 0.051 microg cm(-2) h(-1). Permeated concentrations of PD98059 and LY294002 reduced growth to 13.78 +/- 0.63%. Fish oil plus 2.5% DMSO/ethanol allowed 5.96 +/- 0.9 and 7.7 +/- 1.2 microg cm(-2) of PD98059 and LY294002 to permeate after 48 h.
  
  
  CONCLUSIONS
  PD98059 and LY294002 permeate excised skin at therapeutically useful rates, and also demonstrate growth inhibitory effects on MCF-7 cancer cells. Synergism was noted in co-transport across skin and activity against cancer cells. A formulation based on fish oil is potentially skin friendly; simultaneous permeation of EPA provides further anti-cancer action.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, CF10 3XF, Cardiff, UK.
authors.forename: Zoë
authors.initials: Z
authors.lastname: Davison
authors.forename: Carol
authors.initials: C
authors.lastname: Dutkowski
authors.forename: Julia M W
authors.initials: JM
authors.lastname: Gee
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
authors.forename: Charles M
authors.initials: CM
authors.lastname: Heard
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000502:physiology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D005395:Fish Oils / Q000494:pharmacology; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D010539:Permeability; D014677:Pharmaceutical Vehicles; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D012867:Skin / Q000378:metabolism*; D013552:Swine; D013629:Tamoxifen / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D002867:Chromones; D005395:Fish Oils; D005419:Flavonoids; D009025:Morpholines; D014677:Pharmaceutical Vehicles; D013629:Tamoxifen; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D015118:Eicosapentaenoic Acid; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D004121:Dimethyl Sulfoxide