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The Dunning animal model was used to evaluate endocrine management of prostatic adenocarcinoma. Hypophysectomy, alone or in combination, and orchiectomy plus stilbestrol were the most effective means of suppressing tumor growth. Medical adrenalectomy by aminoglutethimide administration was as effective as surgical ablation. Accessary organ weights bore no direct relationship to the inhibition of tumor growth.

Cells derived from the G-subline of the Dunning R-3327 rat prostatic adenocarcinoma were selected on the basis of their inducibility for alkaline phosphatase (AP) activity by retinoic acid. A p-nitrophenylphosphate-agarose overlay procedure was used to identify AP-inducible clones. The frequency of AP-inducible cells in one rapidly growing tumorigenic clone, designated 9-1C, has remained at 100% during at least 4 months of continuous culture. In culture, 9-1C cells had a mean population-doubling time in log phase of 14 hr. Retinoic acid (10 microM) did not significantly affect the rate of growth in log phase. It did, however, cause the cultures to saturate at a cell density which was 40% lower than that of control cultures. This effect on saturation density was reversible within 24 hr after removing retinoic acid from the medium. Retinoic acid-treated cells occupied greater areas on the culture dish surface, and the cross-sectional area of these cells, measured on dispersed cells by light-scatter flow cytometry, was 35 to 40% greater than that of control cells. The inducibility of 9-1C cells for AP activity decreased as the culture density increased. Cells of the 9-1C clone produced tumors when injected into male and female Fischer X Copenhagen F1 rats. No histological differences were detected between tumors grown in male and female rats. Although the tumors were poorly differentiated, primitive acinar-like structures were observed. Cells staining uniformly positive for AP activity were distributed randomly throughout the tumors. In the acinar-like structures, AP activity was localized only on the apical surfaces of the cells lining the lumens. This was also the site of enzyme activity in acini of the lateral component of the dorsolateral prostate, the source of the original R-3327 tumor. In the lateral prostatic component, AP activity was also found in the basal region of the acini, and the secretory material filling the lumens was strongly positive for the enzyme. These two regions of the tumor acini were negative for AP activity. With the exception of activity in capillaries at the basal surface, the acini of the dorsal component of the dorsolateral prostate were devoid of AP activity.

Explants of embryonic, normal adult, and tumor-containing prostate gland tissue in culture produced outgrowths of cells having an "epithelial" appearance. The fetal cells exhibited by far the highest potential for growth in vitro. Growth of prostate gland adult cells did not appear to depend on the age of the donor. Ultrastructural characteristics of cells from normal human prostates differed from cells derived from adenomatous prostate glands, which had many cytoplasmic characteristics similar to those described in solid tissues. These studies suggest that the characteristics of prostate gland cells in explant primary culture are similar to those in the parent tissues.

The Dunning R3327 transplantable prostate adenocarcinoma in the Copenhagen rat is an acceptable model for the human disease. The G-subline (a rapidly growing carcinoma) and the H-subline (a slow-growing, well-differentiated adenocarcinoma) represent the extremes of differentiation and growth rate of this tumor. Both sublines were found to have one population that was diploid and a second aneuploid population that was hyperdiploid in DNA content. The percentage of hyperdiploid cells was significantly higher in R3327-G tumors than in R3327-H tumors. The tumor cell population ratios were stable in vivo, but the in vitro culture conditions supported only cells with diploid DNA content following four to five subcultures. These predominantly diploid cultured cells, when injected into intact male rats, resulted in tumors that had both diploid and aneuploid cells.

Tumors grown in diethylstilbestrol diphosphate (DES)-treated rats grew significantly more slowly than tumors grown in orchiectomized animals, and tumors grown in orchiectomized animals grew significantly more slowly than tumors grown in controls (intact male rats). When these tumors (phase I) were dispersed and reimplanted into DES-treated, orchiectomized, or control rats in all possible combinations (phase II), a partial selection of androgen-insensitive cells was observed in tumors grown in DES-treated animals. Tumors grown in DES-treated phase I animals responded significantly less to DES treatment or orchiectomy in phase II. In contrast, tumors from phase I orchiectomized animals showed the same responses to orchiectomy in phase II. Since the administration of exogenous testosterone propionate prevented the growth rate inhibitory effects of both DES treatment and orchiectomy, the added effect of DES seemed to be antiandrogenic.