Charles Huggins

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 neo/~i~m 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 of serum is reduced in metastatic 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 (16) 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 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 (1) discovered that there occurs in the spleen and kidney of swine and cattle, in addition to the alkaline phosphatase, a with an activity maximum at pH 4.8. An enzyme believed to be identical with this acid phosphatase was found by Kutscher and Wolbergs (11) to be present in very large amount in the human prostate gland. This finding of great activity of in the prostate gland was confirmed and extended to include prostatic cancer by Gutman, 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 activity. Robinson, Gutman, and Gutman'~I5) summarized the activity levels of 44 patients with carcinoma of the prostate. They concluded that a marked rise in 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. METttODS AND MATERIALS

The thesis of this work may be briefly summarized. In many instances a malignant prostatic tumor is an overgrowth of adult epithelial cells. All known types of adult prostatic epithelium undergo atrophy when androgenic hormones are greatly reduced in amount or inactivated. In this paper evidence is presented that significant improvement often occurs in the clinical condition of patients with far advanced cancer of the prostate after they have been subjected to castration. Conversely, the symptoms are aggravated when androgens are injected. We believe that this work provides a new concept of prostatic carcinoma. The evidence that prostatic carcinoma is often composed of an adult type of epithelium derives from a study of such tissue with respect to the phosphatase which manifests optimum activity at<i>p</i>H5. An important advance in the technic of investigation of the prostate gland was made by Kutscher and Wolbergs,¹who found that

Coarse powders of acid-insoluble matrix of diaphysis and calvarial parietal bone rapidly and consistently transformed fibroblasts into masses of cartilage and bone containing hemopoietic marrow. The transformant was encapsulated by fibroblasts within 24 hr to form a plaque. Transformation was restricted to the central thicknesses of the plaque. Under the stated conditions the alteration of the phenotype, fibroblast to chondroblast, was an unstable transformation, whereas the phenotype change, fibroblast to osteoblast, was stable. The transformation occurred on a rigid timetable of sequences. Measurements of alkaline phosphatase activity and incorporation of radioactive sulfate, phosphate, and calcium were sensitive and quantitative assays for the appearance of the transformed products, cartilage and bone.

No AccessJournal of Urology1 Feb 2002Studies on prostatic cancerI. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate Charles Huggins and M.D. Clarence V. HodgesM.D. Charles HugginsCharles Huggins More articles by this author and Clarence V. HodgesClarence V. Hodges More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(02)80307-XAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail References 1. : Ueber das Vorkommen zweier durch das pH Wirkungsoptimum unterscheidbaren Phosphoesterasen in tierischen Organen. Ztschr. f. physiol. Chem.1934; 229: 125. Google Scholar 2. : Prostatic Carcinoma with Extensive Intraprostatic Calcification. Tr. Am. A. Genito-Urin. Surgeons1938; 31: 363. Google Scholar 3. : Phosphatase Activity of Spleen Extracts. Biochem. J.1934; 28: 529. Google Scholar 4. : Ueber das Vorkommen einer Glycerophosphatase in tierischen Organen. Biochem. Ztschr.1912; 39: 1. Google Scholar 5. : “Acid” Phosphatase and Functional Activity of the Prostate (Man) and Preputial Glands (Rat). Proc. Soc. Exper. Biol. & Med.1938; 39: 529. Google Scholar 6. : An “Acid” Phosphatase Occurring in the Serum of Patients with Metastasizing Carcinoma of the Prostate Gland. J. Clin. Investigation1938; 17: 473. Crossref, Medline, Google Scholar 7. : Significance of Increased Phosphatase Activity at the Cite of Osteoplastic Metastases Secondary to Carcinoma of the Prostate Gland. Am. J. Cancer1936; 28: 485. Google Scholar 8. : The Effect of Castration on Benign Hypertrophy of the Prostate in Man. J. Urol.1940; 43: 705. Link, Google Scholar 9. : Plasma Phosphatase in Osteitis Deformans and in Other Diseases of Bone. Brit. J. Exper. Path.1929; 10: 253. Google Scholar 10. : Convenient Method for Determining Serum and Bile Phosphatase Activity. Canad. M. A. J.1934; 31: 376. Google Scholar 11. : Prostataphosphatase. Ztschr. f. physiol. Chem.1935; 236: 237. Crossref, Google Scholar 12. : Prostataphosphatase. Ztschr. f. physiol. Chem.1938; 255: 169. Google Scholar 13. : Some Effects of Synthetically Prepared Male Hormone (Androsterone) in the Rat. Endocrinology1937; 21: 313. Google Scholar 14. : Blood Phosphatase and van den Bergh Reaction in Differentiation of Several Types of Jaundice. Brit. M. J.1933; 1: 734. Google Scholar 15. : Clinical Significance of Increased Serum “Acid” Phosphatase in Patients with Bone Metastases Secondary to Prostatic Carcinoma. J. Urol.1939; 42: 602. Link, Google Scholar 16. : The Possible Significance of Hexosephosphoric Esters in Ossification. Biochem. J.1923; 17: 286. Crossref, Medline, Google Scholar © 2002 by American Urological Association, IncFiguresReferencesRelatedDetailsCited byBennett J, Foote J, Alphonse P and Hood N (2008) Re: Obesity and Prostate Cancer: Importance of Race and Stage of DiseaseJournal of Urology, VOL. 179, NO. 6, (2481-2482), Online publication date: 1-Jun-2008. Volume 167Issue 2 Part 2February 2002Page: 948-951 Advertisement Copyright & Permissions© 2002 by American Urological Association, IncMetricsAuthor Information Charles Huggins More articles by this author Clarence V. Hodges More articles by this author Expand All Advertisement PDF downloadLoading ...

A study was made of the optimal conditions for the induction of mammary cancer in the rat. 3-Methylcholanthrene was administered via the gastrointestinal tract, and a simple technique was worked out for inducing mammary cancer regularly and rapidly. Under conducive conditions, which were readily reproduced, multiple mammary carcinomas and these tumors only were induced in every rat in repeated experiments in 60 days or less. In the strain of animal employed in the present experiments, the rapid induction of mammary cancer proved to be a function of (a) dosage, (b) the timing of administration of the aromatic hydrocarbon, and (c) a favoring hormonal status of the recipient. Most of the established tumors were hormone-dependent because they diminished markedly in size after hormone withdrawal through ovariectomy or hypophysectomy. Similar regression of the tumors was frequently achieved by the administration of dihydrotestosterone. Shrinkage of the cancers was accompanied by atrophic changes. Experimental mammary tumors with these physiologic characteristics have not been recognized hitherto. The minority of mammary cancers continued to grow after ovariectomy; these are hormone-independent tumors and tumors of this sort had a characteristic cytologic appearance following modification of the endocrine state. The cell population of a single tumor was not always uniform in its response to appropriate hormonal modifications. In certain tumors in response to changes in the endocrine status of the host many of the cells underwent atrophy whilst other adjacent cells in the same tumor continued to grow so that the net result was a hormone-independent tumor. Hypophysectomy was the most effective method found to induce regression of mammary cancer in the present experiments.