Effect of antiandrogen and/or antiestrogen blockade on human prostate epithelial and stromal cell protein synthesis.
To evaluate the role of small amounts of DHT in prostate tissue as a stimulus to epithelial cell growth (protein synthesis) we studied tissue from patients given various androgen-blocking drugs prior to transurethral resection of the prostate (TURP) and measured epithelial protein synthesis and DHT in the tissue specimens. We also studied the effects on stromal cell protein synthesis of an antiestrogen, tamoxifen. Test drugs prior to TURP included Megace 160 mg per day, Megace 160 mg per day plus Tamoxifen 40 mg per day, Megace 160 mg a day plus ketoconazole 1200 mg per day and tamoxifen 40 mg/day. The tissue was processed immediately and epithelial and stromal cells separated by digestion of tissue with 0.5% collagenase. After separation, epithelial cells were labeled with either [3H]leucine or L-[35S]methionine. Stromal cells were labelled with [3H]proline. DHT was measured in whole prostate tissue. Megace alone and Megace plus tamoxifen significantly decreased both [3H]leucine incorporation into protein and tissue concentration of DHT; Megace plus ketoconazole significantly decreased L-[35S]methionine incorporation into protein and DHT. Tamoxifen significantly decreased stromal protein synthesis. When the data correlating DHT with epithelial protein synthesis using both labeling techniques were combined, the curves were parallel and a strong correlation was noted between DHT and protein synthesis over a wide range of values (P less than 0.001). These results suggest that in hormone-dependent prostate cancer even small amounts of prostate DHT such as may occur from adrenal androgens following castration may significantly stimulate growth of the tumor epithelial cells. Since tamoxifen decreased stromal protein synthesis, estrogen is likely a significant growth stimulus to the increased stromal mass characteristic of benign prostatic hypertrophy.
D013196:Dihydrotestosterone / Q000096:biosynthesis; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008535:Megestrol / Q000031:analogs & derivatives* / Q000494:pharmacology; D019290:Megestrol Acetate; D011467:Prostate / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis; D013629:Tamoxifen / Q000494:pharmacology*
D013196:Dihydrotestosterone; D013629:Tamoxifen; D008535:Megestrol; D007654:Ketoconazole; D019290:Megestrol Acetate