CIRCUMVENTION OF MULTIDRUG-RESISTANCE IN MURINE FIBROSARCOMA AND COLON-CARCINOMA CELLS BY TREATMENT WITH THE ALPHA-ADRENOCEPTOR ANTAGONIST FUROBENZAZEPINE

The purpose of this study was to determine whether agonists and antago nists of alpha-adrenoceptors that affect calcium fluxes and protein ki nase C signal transduction alter the chemosensitivity of cancer cells that exhibit multidrug resistance (MDR). The effects of nine alpha-adr enoceptor antagonists or antagonists on the in vitro chemosensitivity of the UV-2237 murine fibrosarcoma and its doxorubicin-selected MDR va riants (UV-2237-R1 and UV-2237-R10) were examined. Noncytotoxic concen trations of the alpha-adrenoceptor antagonist furobenzazepine enhanced the antitumor activity of doxorubicin, actinomycin D, vinblastine and vincristine, but not 5-fluorouracil. Similar effects of furobenzazepi ne were also observed in recently established doxorubicin-resistant MD R variants of the CT-26 murine colon carcinoma. The chemosensitizing e ffect of furobenzazepine was associated with an increase in intracellu lar 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-glycop rotein-mediated experimental MDR phenotype.