Studies on Prostatic Cancer: I. The Effect of Castration, Of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate
Carcinoma of the prostate gland is peculiarly favorable for endocrine investigation since frequent serial observations of the activity of phosphatases in serum were found to provide objective indices of activity of the neoplasm when the enzymes were increased in amount above normal. In the present paper data are given for the values of serum phosphatases in carcinoma of the prostate and in normal men. We shall demonstrate that the acid phosphatase of serum is reduced in metastatic carcinoma of
... tatic carcinoma of the prostate by decreasing the activity of androgens through castration or estrogenic injections and that this enzyme is increased by injecting androgens. We have been unable to find previous observations indicating any relationship of hormones to carcinoma of the prostate gland. An enzyme capable of hydrolyzing phosphoric esters was discovered by Grosser and Husler (4) in intestinal mucosa and kidney. Robison (I6) found that this enzyme was particularly high in activity in growing bone and cartilage and that its activity was greatest at pH 9 to 9.5-This "alkaline phosphatase" was found by Kay (9) to be increased in the serum in certain bone diseases including metastasis of neoplasms to bone and later work has shown that among these conditions is carcinoma of the prostate. Davies (3) and Bamann and Riedel (I) discovered that there occurs in the spleen and kidney of swine and cattle, in addition to the alkaline phosphatase, a phosphatase with an activity maximum at pH 4.8. An enzyme believed to be identical with this "acid phosphatase" was found by Kutscher and Wolbergs (II) to be present in very large amount in the human prostate gland. This finding of great activity of acid phosphatase in the prostate gland was confirmed and extended to include prostatic cancer by Gutrnan, Sproul, and Gutman (7) . The serum of certain patients with disseminated prostatic carcinoma was found by Gutman and Gutman (6) and Barringer and Woodard (2) to exhibit increased acid phosphatase activity. Robinson, Gutman, and Gutman (I5) summarized the acid phosphatase activity levels of 44 patients with carcinoma of the prostate. They concluded that a marked rise in acid phosphatase in serum is associated with the appearance or spread of roentgenologically demonstrable skeletal metastases and implies dissemination of the primary tumor and thus is of unfavorable prognostic significance. * This investigation was aided by a grant from the Committee on Research in Problems of Sex, the National Research Council. METHODS AND MATERIALS The phosphatase activity of serum was determined by the method of King and Armstrong (io) using 0.005 M disodium monophenylphosphate as substrate. The buffers used were 0.05 M barbital-sodium at pH 9.3, and o.i M S6rensen's citrate-HC1 or Walpole's 0.2 N sodium acetate-acetic acid buffers at pH 5-All serums were tested in duplicate and were added directly to buffer-substrate solutions without dilution; they were incubated at 37.5 ~ C. for 3 ~ minutes. Precautions were observed that all solutions were at this temperature before testing. Blanks were run by adding the protein precipitant to the buffer-substrate solution before adding serum. Colorimetric procedures were carried out with the Evelyn photoelectric colorimeter using a 6600 A filter. The results are expressed in King and Armstrong units, a unit being defined as that degree of phosphatase activity which at pH 9.3 (or pH 5.0, respectively) and 37.5 ~ C. will liberate i mgm. of phenol from the specified buffer-substrate solution in one-half hour. Phosphatase determinations at pH 5 and 9.3 were made on the serum of 4 ~ normal men, of 2I men with benign prostatic hypertrophy, and of 47 men with carcinoma of the prostate. The diagnosis of carcinoma of the prostate gland was derived from one or more of the following procedures: rectal palpation, cystoscopic examination, transurethral resection with microscopic examination, or roentgenologic evidence of skeletal metastases. Necropsy was obtained in 2 cases. All patients had x-ray studies of the bony pelvis. Eight patients who had carcinoma of the prostate with skeletal metastases and with moderate or great elevation of acid phosphatase of serum values above 20 units in Ioo cc. were selected for intensive study in the hospital. Each patient also had elevation of alkaline phosphatase in the serum. Both of these enzymes were determined on the serum 3 times weekly for many weeks. Bilateral castration was carried out in all. Five patients were injected with stilbestrol, i mgm. 293 Research. on August 23, 2017.