ESTABLISHMENT OF DOXORUBICIN-RESISTANT HUMAN BLADDER-CANCER CELL-LINE(BIU-87 ADMR) AND ITS MECHANISM OF MULTIDRUG-RESISTANCE/

Objective To establish a doxorubicin-resistant human bladder cancer ce ll line, BIU-87/ADMR, and to study its biological characteristics and mechanism of drug resistance. Methods A human bladder cancer cell line resistant to doxorubicin, BIU-87/ADMR, has been established in vitro by exposing BIU-87 parent cells to progressively increasing concentrat ions of the drug over a period of 8 months. The cell line has been cha racterized in terms of growth kinetics, morphology, cross-resistance t o other anticancerous agents, pharmacokinetics of daunorubicin and exp ression of P-glycoprotein (P-gp) which is closely related to the MDR p henotype. Results The BIU-87/ADMR cell line was 6. 3 times more resist ant to doxorubicin than the parent BIU-87. II exhibited cross-resistan ce to doxorubicin derivatives (epirubicin, daunorubicin), vincristine and etoposide, bur not to cisplatin and mitomycin C. Compared to the p arent cells, the resistant cells have a slower growth rate and lower c onfluent density. Unlike the parent BIU-87, about 75% of the BIU-87/AD MR cells showed a positive reaction with monoclonal antibody against P -gp, JSB-1. Intracellular drug accumulation studies with fluorescence spectrometry indicated that the resistance exhibited by the BIU-87/ADM R line was mainly caused by an increased active efflux. Conclusions Th e results suggest that MDR is an important phenomenon in bladder cance r and that more than one pathway of MDR may be present in human bladde r cancer cell lines. BIU-87/ADMR may be a useful model for the develop ment of new chemotherapeutic strategies in overcoming drug-resistance in the treatment of bladder cancer.