title: Circumvention of multidrug-resistance in murine fibrosarcoma and colon-carcinoma cells by treatment with the alpha-adrenoceptor antagonist furobenzazepine.
abstract: The purpose of this study was to determine whether agonists and antagonists of alpha-adrenoceptors that affect calcium fluxes and protein kinase C signal transduction alter the chemosensitivity of cancer cells that exhibit multidrug resistance (MDR). The effects of nine alpha-adrenoceptor antagonists or antagonists on the in vitro chemosensitivity of the UV-2237 murine fibrosarcoma and its doxorubicin-selected MDR variants (UV-2237-R1 and UV-2237-R10) were examined. Noncytotoxic concentrations of the alpha-adrenoceptor antagonist furobenzazepine enhanced the antitumor activity of doxorubicin, actinomycin D, vinblastine and vincristine, but not 5-fluorouracil. Similar effects of furobenzazepine were also observed in recently established doxorubicin-resistant MDR variants of the CT-26 murine colon carcinoma. The chemosensitizing effect of furobenzazepine was associated with an increase in intracellular accumulation of anticancer drugs. Furobenzazepine did not compete with [H-3]azidopine for photoaffinity labeling of P-glycoprotein, but it did produce a transient 30% reduction of P-glycoprotein in the MDR cells. These data indicate that furobenzazepine can reverse a P-glycoprotein-mediated experimental MDR phenotype.
authors.affiliation: SMITHKLINE BEECHAM PHARMACEUT,KING OF PRUSSIA,PA 19406.
authors.forename: D
authors.initials: D
authors.lastname: Fan
authors.forename: G
authors.initials: G
authors.lastname: Poste
authors.forename: R
authors.initials: R
authors.lastname: Ruffolo
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.forename: C
authors.initials: C
authors.lastname: Seid
authors.forename: L
authors.initials: L
authors.lastname: Earnest
authors.forename: T
authors.initials: T
authors.lastname: Campbell
authors.forename: R
authors.initials: R
authors.lastname: Clyne
authors.forename: P
authors.initials: P
authors.lastname: Beltran
authors.forename: I
authors.initials: I
authors.lastname: Fidler