The proliferative effect of "anti-androgens" on the androgen-sensitive human prostate tumor cell line LNCaP.
The effect of steroidal and nonsteroidal "anti-androgens" on the proliferative capacity of androgen-sensitive LNCaP-FGC human prostate tumor cells in culture was studied using charcoal-dextran stripped human serum-supplemented media. Cyproterone and medroxyprogesterone acetates, flutamide, hydroxyflutamide, and anandron (R23908) were administered alone at concentrations between 3 X 10(-12) and 3 X 10(-6) M. Results indicated that although medroxyprogesterone induced maximal proliferation at 3 X 10(-9) M, the other "anti-androgens" (with the exception of flutamide that was ineffective) were effective at 3 X 10(-8) M and higher concentrations; the amplitude of the proliferative response by these compounds was comparable to that elicited by estradiol-17 beta (3 to 5-fold over control). None of the anti-androgens tested triggered the shutoff effect characteristic of androgen action. When 3 X 10(-10) M DHT and the above mentioned anti-androgens were administered simultaneously, a synergistic pattern was seen; on the contrary, 3 X 10(-8) M DHT cancelled the proliferative effect of each of the anti-androgens when administered simultaneously. The relative binding affinity of these anti-androgens to androgen receptors present in LNCaP-FGC cells did not correlate well with their proliferative efficiency. The data collected were interpreted within the premises of the negative control hypotheses for the regulation of cell proliferation in metazoans. Within those premises, results became compatible with the notion that first, "anti-androgens" elicited the proliferation of androgen-sensitive cells by neutralizing the effect of a serum-borne inhibitor (androcolyone-I); this event seems not to be mediated by androgens receptors. Second, anti-androgens did not trigger a proliferative shutoff response like androgens do, i.e. the proliferative pattern induced by anti-androgens was comparable to that elicited by estrogens and progestins. Third, when administered simultaneously with 3 X 10(-10) M DHT, anti-androgens behaved synergistically. Fourth, the DHT-induced shutoff effect consistently overrode the proliferative effect generated by anti-androgens and estrogens when added alone. Finally, taken together these results raise important questions regarding the therapeutic role of anti-androgens in prostate cancer.
Olea
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Tufts University Health Science Schools, Department of Anatomy and Cellular Biology, Boston, Massachusetts 02111.
Sakabe
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K
Soto
A M
AM
Sonnenschein
C
C
D000728:Androgens / Q000276:immunology* / Q000494:pharmacology; D000906:Antibodies / Q000276:immunology / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005485:Flutamide / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008297:Male; D009277:Nandrolone / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000276:immunology; D045165:Testosterone Congeners; D014407:Tumor Cells, Cultured
D000728:Androgens; D000906:Antibodies; D011944:Receptors, Androgen; D045165:Testosterone Congeners; D013196:Dihydrotestosterone; C014290:hydroxyflutamide; D004958:Estradiol; D009277:Nandrolone; D005485:Flutamide; C100075:mibolerone