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Using a fluorometric assay, nonspecific proteolytic activity and plasminogen activator were measured in transplantable tumors of the dorsal prostate of Nb rats. Nonspecific proteolytic activity in prostatic tumors did not differ significantly from that measured in normal dorsal prostate, whereas plasminogen activator activity, undetectable in the latter tissue, was readily measurable in the tumors. Furthermore, plasminogen activator activity in prostatic tumors characterized by hormone-insensitive growth was 8-fold higher than in tumors characterized by androgen-stimulated growth. In both typess of tumors, the plasminogen activator activity per mg protein was highest in the lysosomal fractions. The results indicate that plasminogen activator may be a useful marker for discriminating between androgen-stimulated and autonomous prostatic tumors.

A transplantable prostatic adenocarcinoma derived from the dorsal lobe of the prostate gland of an Nb rat was analyzed for the concentration of nuclear androgen-binding sites and the presence of acid phosphatase activity. When extracts of nuclei from normal prostatic tissue were labelled with [1,2-3H]dihydrotestosterone in the absence and presence of competitor, two types of specific binding were observed: type 1 was characterized by an association constant (Ka) of 6 x 10(7) M-1 and involved a molecule that was excluded from Sephadex G-200; type 2 was characterized by a Ka of 3 x 10(8) M-1 and depended on a binding component that was retained by Sephadex G-200. Nuclei from androgen-stimulated tumors contained reduced concentrations of both androgen-binding components, whereas nuclei from autonomous tumors had only a trace amount of type 1 sites and were entirely devoid of type 2 sites. In all tumors the acid phosphatase activity per mg of protein was markedly elevated. Relative to normal, the activity of this enzyme was 140% and 350% higher in androgen-stimulated and autonomous tumors, respectively. These findings indicate that prostatic tumors are characterized by a decrease in nuclear androgen-binding, and an increase in specific activity of acid phosphatase, and also that such changes are more pronounced in autonomous than in androgen-stimulated tumors.

Carcinoma in the dorsal prostate of Nb rats was produced by prolonged treatment with androgen or androgen plus estrogen. The most effective combination was androgen followed by estrogen, resulting in an incidence of 50% in 10 rats. In such a case, the rats did not show evidence of androgenization. Transplants were usually not sensitive to hormones, but an estrogen-dependent tumor (Nb-2Pr-E) was successfully transplanted in estrogenized hosts. Cells of estrogen-dependent tumors did not grow in males but remained dormant and could be stimulated to grow after many months by estrogen treatment. The resulting tumors remained estrogen dependent, with one exception which was autonomous. Tumors regressed following estrogen removal but eventually showed a spontaneous regrowth which was then found to be autonomous. In the case of growing tumors, the reduction of estrogen to subthreshold doses for maximal growth allowed stationary or only slow growth of the tumors, but these remained estrogen dependent. Estrogen-dependent tumors responded to tamoxifen treatment by a cessation of tumor growth or regression despite continued estrogen treatment. Tumor regrowth eventually took place after prolonged tamoxifen treatment, but the tumors remained estrogen dependent when transplanted.

The development of adenocarcinoma of the dorsal prostate of Nb rats following prolonged treatment with pellets of testosterone propionate alone or with esterone allowed the establishment of transplantable tumor models. Whereas most transplants were autonomous and not influenced by hormones, one estrogen dependent tumor was studied in detail. This tumor would only grow in estrogenised hosts, cells remaining dormant in normal animals. Removal of estrogen from animals with growing tumors led to tumor regression but with progression and eventual regrowth of tumors which were autonomous. Replacement with lower doses of estrogen reduced the extent of regression and prevented autonomous change. When a regressed estrogen dependent tumor was exposed to prolonged treatment with testosterone propionate pellets, the eventual regrowth was found to be androgen dependent and would not grow in estrogenised animals. Progression could apparently be directed by this procedure from estrogen to androgen dependency.

Mammary carcinoma was induced in female Nb rats by implanting pellets of estrone at 25-28 days of age, and prostatic cancer was induced in male rats of the same strain by repeatedly implanting pellets of testosterone propionate. Feeding semipurified diets containing either 3% or 20% corn oil did not significantly affect the incidence or yield of mammary tumors, although tumors tended to appear somewhat earlier in animals on the high-fat diet, confirming the report of Dunning et al. published nearly 40 years ago. The yield of prostatic tumors was too low to draw any conclusions with respect to dietary fat. Hormonally induced mammary tumors appear to be less responsive to dietary fat than those induced by commonly used chemical carcinogens.

Androgen-stimulated tumors of the dorsal prostate were derived from an estrogen-dependent tumor of Nb rats (Nb-2Pr-E). The change followed repeated androgen treatments in a rat bearing a tumor which had regressed after estrogen removal. The eventual tumor regrowth provided tumor transplant lines, Nb-2Pr-A, which grew in normal or androgenized males, slowly in castrates, but not in estrogenized females. The Nb-2Pr-A growing tumors regressed after treatment with estrogen, and tumors which eventually regrew were autonomous. Slow tumor growth in castrated animals also responded to estrogen treatment. Tamoxifen, an antiestrogen, caused tumors growing in males to become stationary or regress. Regrowth of tumors after they had responded to tamoxifen again responded to castration or estrogen. Tumors which escaped from estrogen treatment or were autonomous did not respond to tamoxifen. The most effective sequence for treatment was tamoxifen followed by castration and, finally, estrogen. Tamoxifen treatment or castration allowed tumors to remain hormone responsive, whereas initial estrogen treatment prevented response to subsequent therapy and led to an autonomous change.

The low spontaneous incidence of grossly recognizable adenocarcinomas of the dorsal lobe of the prostate in Nb rats over 13 months old (0.45%) was increased to 18.38% in 130 rats by prolonged treatment with pellets of suitable sex hormones. Although testosterone propionate alone was effective, if the testosterone propionate was combined with treatment by estrone carcinomas of the prostate occurred after a shorter interval. Tumors tended to metastasize and transplanted readily, and all were autonomous, with a single exception that exhibited the growth pattern of a typical estrogen-dependent tumor.