ROLE OF RAS ONCOGENE IN ADRIAMYCIN RESISTANCE IN HUMAN PROSTATE TUMOR-CELLS

We have previously isolated a drug-resistant, [PC3(R)], variant of hum an prostate PC3 cell line, which showed significant resistance (>10-fo ld) to adriamycin. No known mechanisms of drug resistance were found; however, resistant cells expressed more bcl2, c-myc, and ms oncogenes compared to the sensitive cells. In this study, we found that buthioni ne sulfoximine (BSO), an inhibitor of gamma-glutamyl-cysteine syntheta se, decreased glutathione levels by 80-90% in both cell lines. BSO tre atment down-modulated Ras protein only in PC3(R) cells and caused a 4- fold sensitization of PC3(R) cells to adriamycin without affecting PC3 (W) cells. Farnesol treatment also inhibited expression of Ras protein and concomitantly reversed adriamycin resistance in PC3(R) cells, ind icating that altered levels of ras expression plays an important role in drug resistance in PC3(R) cells.