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Growth Inhibition of Human Prostate Cells in Vitro by Novel Inhibitors of Androgen Synthesis

Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201 [G. T. K., J. N., J-s. L., Y-z. L., C. S., A. M. H. B.], and the Laboratories for Reproductive Biology and the Departments of Pediatrics and Biochemistry, University of North Carolina, Chapel Hill, North Carolina 27599 [J. A. K., E. M. W.]

The long-standing strategy for the treatment of metastatic prostate cancer has been to reduce androgenic stimulation of tumor growth by removal of the testes, the primary site of testosterone synthesis. However, a low level of androgenic stimulation may continue, even after castration, by the conversion of adrenal androgens to 5-dihydrotestosterone (DHT) in the prostate tumor cells. Two important enzymes of the androgen biosynthetic pathway are 17-hydroxylase/C_17,20-lyase, which regulates an early step in the synthesis of testosterone and other androgens in both the testes and adrenal glands, and 5-reductase, which converts testosterone to the more potent androgen, DHT, in the prostate. We have identified new inhibitors of these enzymes that may be of use in achieving a more complete ablation of androgens in the treatment of metastatic prostate cancer. Three derivatives of androstene were shown to inhibit 17-hydroxylase/C_17,20-lyase with potencies 2–20-fold greater than that of ketoconazole, a previously established inhibitor of this enzyme. Derivatives of pregnane and pregnene displayed activities against 5-reductase that were comparable to that of N-(1,1-dimethyl-ethyl)-3-oxo-4-aza-5-androst-1-ene-17ß-carboxamide. All of the 5-reductase inhibitors were able to at least partially inhibit the mitogenic effect of testosterone in either histocultures of human benign prostatic hypertrophic tissue or in cultures of the LNCaP human prostatic tumor cell line. For these compounds, it appears that this inhibition can be attributed to a reduction of DHT synthesis in these cultures, because no inhibitory effect was observed in DHT-treated cultures, and none of the compounds had a cytotoxic effect. Surprisingly, one of the inhibitors of 17-hydroxylase/C_17,20-lyase, 17ß-(4-imidazolyl)-5-pregnen-3ß-ol, was also able to inhibit the mitogenic effect of testosterone in both the histoculture and cell culture assays and had an effect against DHT as well. In transcriptional activation assays, it was found that this compound is an antagonist of both the wild-type androgen receptor and the mutant androgen receptor, which is present in LNCaP cells. In conclusion, the abilities of these compounds to inhibit androgen synthesis and, in some cases, to exert antiandrogen activity, did in fact translate to an inhibitory effect on the growth of human prostatic tissue in vitro, suggesting their potential utility in the treatment of prostatic cancer.

² Present address: Research Institute of Life Science, Snow Brand Milk Products Company, Ltd., Shimotsuga-gun, Tochigi 329-05, Japan.

³ Present address: Central Research, Pfizer, Inc., Groton, CT 06340.

⁴ To whom requests for reprints should be addressed, at Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Room 4-002 Bressler Building, 655 West Baltimore Street, Baltimore, MD 21205.

Received 6/ 3/96. Accepted 9/ 3/96.

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