SPECIFIC MULTIDRUG-RESISTANCE PATTERN AND EFFLUX OF RHODAMINE(123) INANDROGEN-INDEPENDENT PROSTATE CARCINOMA-CELLS

Hormone independent growing prostate carcinoma cells display an enhanc ed resistance against different cytotoxic agents. Specific resistance mediators, as the expression of the membrane-bound efflux pump P-glyco protein have so far received only minor attention. We examined the res istance patterns in hormone sensitive and hormone independent growing sublines of the Dunning rat prostate carcinoma against the P-glycoprot ein substrates vinblastine, doxorubicin, taxol, etoposide and colchici ne, as well as against cisplatin and methotrexate, which are not trans ported by this protein. Additionally we studied the kinetics of the ac tive transmembraneous efflux of the fluorescent P-glycoprotein substra te rhodamine 123 by FAGS. Compared to the hormone sensitive subline G, the hormone insensitive sublines display a 3- to 26-fold increased re sistance against the P-glycoprotein substrates, whereas all cell lines show comparable resistance levels against methotrexate and cisplatin. By addition of verapamil, the 9- to 10-fold increased vinblastine res istance and the 7- to 26-fold increased taxol resistance could be almo st totally overcome. Furthermore, rhodamine 123 was effectively extrud ed by the hormone independent cell lines, but not by the G cells. Our results point to a possible expression of P-glycoprotein or another ve rapamil sensitive efflux pump, which might be crucial in the enhanced cytotoxic drug resistance in androgen independent growing sublines.