In vitro effects on MCF-7 breast cancer cells of signal transduction inhibitor/tamoxifen/eicosapentaenoic acid combinations and their simultaneous delivery across skin

Purpose. 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 mu g cm(-2) h(-1), respectively; applied simultaneously, 0.18 +/- 0.045 and 0.49 +/- 0.051 mu g 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 mu g cm(-2) of PD98059 and LY294002 to permeate after 48 h. 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.