Response of rat and human prostatic cancers to the novel 5α‐reductase inhibitor, SK&F 105657

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 5α‐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 5α‐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., >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 5α‐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 5α‐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 5α‐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 5α‐reductase activity.