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Testosterone-mediated Increase in 5-Dihydrotestosterone Content, Nuclear Androgen Receptor Levels, and Cell Division in an Androgen-independent Prostate Carcinoma of Noble Rats¹

Department of Biology, Tufts University School of Arts and Sciences, Medford, Massachusetts 02155 [S-M. H., H. S. K. S.]; Departments of Pathology and Anatomy and Cellular Biology, Tufts University Schools of Medicine and Veterinary Medicine, Boston, Massachusetts 02111 [I. L., P. W. L. K., F. B. M.]; and Department of Anatomy and Cellular Biology, Tufts University Schools of Medicine and Veterinary Medicine, Boston, Massachusetts 02111 [D. D.]

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-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-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-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.

¹ Supported in part by Grant CA-15776 from the National Cancer Institute and Grant PCM8310200 from the National Science Foundation.

² To whom requests for reprints should be addressed.

Received 3/16/87. Revised 7/31/87. Revised 10/22/87. Accepted 10/26/87.