Testosterone-mediated increase in 5 alpha-dihydrotestosterone content, nuclear androgen receptor levels, and cell division in an androgen-independent prostate carcinoma of Noble rats.

An androgen-independent, transplantable prostate carcinoma line (AIT), originally derived from the dorsolateral prostate (DLP) of Noble rat, was implanted into orchiectomized Noble rats and its response to androgen stimulation was studied and compared to that of the regenerating DLP tissue in sexually ablated rats. AIT tumors carried in castrated hosts displayed a high basal level of proliferative activity (mitotic index (MI), 15.0 +/- 0.5) while DLP tissue in untreated castrates exhibited no proliferative activity. Following androgen stimulation by testosterone capsule implantation into host rats, the AIT responded with a marked increase in cell proliferation; MI values doubled to 30.0 +/- 2.9 on Day 5 following androgen stimulation. This androgen-induced increase in MI values was coincident with elevations in nuclear androgen receptor (20-fold increase) and 5 alpha-dihydrotestosterone content (3-fold increase) in the tumor. However, by Day 10 following androgen treatment, indices of cell proliferation in the AIT declined to pre-androgen-stimulated levels (MI, 14.8 +/- 1.9) despite the continued elevations in nuclear androgen receptor and tissue 5 alpha-dihydrotestosterone contents. Parallel changes in MI were also observed in the normal regenerating DLP following androgen stimulation. MI values in this tissue increased from nondetectable levels to 38.1 +/- 4.7 on Day 5 but declined to relatively low levels (4.5 +/- 0.9) by Day 10 following androgen replacement. Taken together these findings led us to conclude that the AIT carried in castrates is capable of responding to testosterone in a manner similar to that observed for androgen-stimulated DLP of sexually ablated rats. Thus, in both the neoplastic and regenerating tissues, the initial response to androgen is characterized by a marked enhancement of cell proliferation which was correlated with an increase in androgen receptor and 5 alpha-dihydrotestosterone content. However, like its tissue of origin, the AIT possesses mechanisms which act to limit androgen-induced cell division despite continued elevations in key parameters of androgen activation.

Androgen receptor levels and androgen contents in the prostate lobes of intact and testosterone-treated Noble rats.

Plasma testosterone (T) levels were correlated with androgen receptors, tissue content of T, and 5 alpha-dihydrotestosterone (DHT) in the three anatomically-discrete prostate lobes of intact and castrated Noble (Nb) rats bearing T-filled silastic capsules. Differences in androgen receptor content and tissue androgen levels were observed among the three prostatic lobes of intact Nb rats. Total (cytosolic and nuclear) androgen receptor levels were highest in the ventral prostate followed by the dorsolateral and anterior prostate lobes. In the ventral and anterior prostate, androgen receptors were found to be equally distributed between cytosols and nuclear extracts, whereas in the dorsolateral prostate, androgen receptors were predominantly nuclear (cytosolic: nuclear = 1.5). The ventral prostate had the highest total androgen content and DHT was the major tissue androgen in all three lobes. The ratio of tissue DHT:T varied among the lobes; the highest value was observed in the dorsolateral prostate. The higher proportions of nuclear androgen receptor, as well as the elevated tissue DHT:T found in the dorsolateral prostate compared to other lobes, suggest that differences in the androgen activation process may exist between the dorsolateral prostate and other prostatic lobes. Despite lower plasma and tissue T levels, the DHT content, weight and cytodifferentiation in all lobes of T-treated castrated rats closely approximated the situation found in intact animals. Total androgen receptor levels were, however, elevated in all prostatic lobes of T-treated, castrated rats as compared to intact controls. These increases were primarily attributed to the augmented levels of androgen receptor in the nuclear extracts of the three prostate lobes. Exposure of the prostate to a constant level of T, produced by silastic implantation, might be responsible for the higher total androgen receptor levels and enhanced nuclear androgen receptor retention found in the prostates of T-treated, castrated rats.