MULTIDRUG-RESISTANCE IN ANDROGEN-INDEPENDENT GROWING RAT PROSTATE CARCINOMA-CELLS IS MEDIATED BY P-GLYCOPROTEIN

Prostate carcinomas are in general resistant against virtually all cyt otoxic drugs. Up to now it has not been thoroughly evaluated whether s pecific resistance factors, such as the expression of the MDR1 play a role in this multi-agent resistance and whether there is a link betwee n drug resistance and hormone-independent growth. We investigated the resistance patterns of a hormone-sensitive and four hormone-independen t Dunning rat carcinoma sublines against four drugs which are substrat es of P-glycoprotein (vinblastine, taxol, doxorubicin, and etoposide) and two agents (methotrexate and cis-platinum) which are not transport ed by this efflux pump. All hormone-insensitive sublines, AT.1, AT.3.1 ., MatLu and Mat LyLu, continuously showed a clearly enhanced resistan ce (3- to 26-fold) against the P-glycoprotein substrates, compared to the hormone-sensitive subline G, Only two of the androgen-independent sublines displayed enhanced resistance against methotrexate, whereas a ll of them were more sensitive against cisplatin than the androgen-sen sitive G cells. By addition of verapamil the resistance against vinbla stine (9- to 10-fold) and taxol (6.7- to 26.7-fold) in the hormone-ins ensitive cells could be almost totally reversed. Furthermore, the fluo rescent P-glycoprotein substrate rhodamine-123 was effectively pumped out of the four tested hormone-independent cell lines, whereas the hor mone-sensitive G cells were unable to extrude the dye. By reverse tran scriptase polymerase chain reaction (RT-PCR) with primers specific for the rat mdr1b gene, the homologue to the human MDR1 gene, we could ea sily detect mdr1b expression in the androgen independent cell lines, b ut not in the G cells. Our results suggest that the product of the rat mdr1b gene is involved in the multidrug resistance of androgen-indepe ndent Dunning prostate carcinoma cells.