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.