P-GLYCOPROTEIN-MEDIATED MULTIDRUG-RESISTANCE IS MODULATED BY PRETREATMENT WITH CHEMOSENSITIZERS IN HCT-8 CARCINOMA-CELLS IN-VITRO

The effects of pretreatment with the multidrug resistance (MDR) modula tors verapamil (VPM), tamoxifen (TMX), cyclosporin A (CsA), and SDZ PS C833 (PSC) on drug sensitivity of the P-glycoprotein (Pgp) expressing human ileocecal carcinoma cell line HCT-8 is described. Following pret reatment of 2, 16 and 48 h with the individual modulators, rhodamine 1 23 efflux (RHO), transepithelial vinblastine transport (VIN) across tr eated HCT-8 monolayers, and chemosensitivity to doxorubicin (DOX) were determined and compared to Pgp protein expression and phosphorylation . After 2 h, VPM, TMX, CsA and PSC inhibited RHO efflux and VIN transp ort and increased the chemosensitivity of HCT-8 to DOX significantly, Prolonged exposure failed to further increase inhibition of Pgp-mediat ed transport, but in contrast maximized phosphorylation of Pgp (16 h) and Pgp protein expression (48 h), respectively.