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Response of rat and human prostatic cancers to the novel 5 alpha-reductase inhibitor, SK&F 105657.

Abstract
The response of two androgen-responsive rat prostatic cancers (i.e., Dunning R-3327 H and G sublines) and one androgen-responsive human prostatic cancer (i.e., PC-82) to the 5 alpha-reductase inhibitor, SK&F 105657, was tested in vivo. SK&F 105657 was administered orally twice a day at a dose of 25 or 50 mg/kg/dose. The rat R-3327 G tumor and the human PC-82 tumor have a low to undetectable level of tissue 5 alpha-reductase activity and both responded to SK&F 105657 treatment with a reproducible inhibition of tumor growth. Associated with this antitumor effect was a major decrease (i.e., greater than 70%) in tissue dihydrotestosterone (DHT) content in both tumors. By contrast, the rat R-3327 H prostatic cancer has a much higher level of tissue 5 alpha-reductase activity, and neither tumor DHT content nor growth of the tumor was inhibited by treatment with SK&F 105657. Drug treatment of rats bearing R-3227 H tumors resulted in a similar reduction in the DHT content, wet weight, and DNA content of the ventral prostate as that produced in R-3327 G tumor-bearing rats which experienced an antitumor response. These results suggest that SK&F 105657 can produce antitumor effects if a substantial reduction in tissue DHT is achieved. Such reduction in tissue DHT, secondary to inhibition of the tissue 5 alpha-reductase enzyme, appears to be more difficult to achieve in tumors than in the normal prostate. In order to achieve such a DHT reduction in tumor tissue, prostatic cancers with low 5 alpha-reductase activity could be treated with SK&F 105657 on a dose regimen that lowers serum DHT to surgical castration levels, while concomitantly inhibiting the already low tumor tissue 5 alpha-reductase activity.
AuthorsJ C Lamb, M A Levy, R K Johnson, J T Isaacs
JournalThe Prostate (Prostate) Vol. 21 Issue 1 Pg. 15-34 ( 1992) ISSN: 0270-4137 [Print] United States
PMID1641369 (Publication Type: Journal Article)
Chemical References
  • 5-alpha Reductase Inhibitors
  • Androstadienes
  • Antineoplastic Agents
  • Dihydrotestosterone
  • epristeride
Topics
  • 5-alpha Reductase Inhibitors
  • Androstadienes (pharmacology)
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Dihydrotestosterone (metabolism)
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Prostatic Neoplasms (drug therapy, enzymology, pathology)
  • Rats
  • Rats, Inbred Strains
  • Substrate Specificity
  • Tumor Cells, Cultured (drug effects)

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