Two Principles in Endocrine Therapy Ofcancers: Hormone Deprival and Hormone Interference1

Two Principles in Endocrine Therapy ofCancers: Hormone D eprival and H orm on e Interference1

CHARLES HUGGINS (The Ben May Laboratory for Cancer Re8earch, University of Chicago, Chicago, Illinois)

SUMMARY Hormones, or synthetic substances exerting physiologic effects similar thereto, are of crucial significance for growth of 7 hormone-dependent cancers of man and the animals. Two opposite sorts of change of the hormonal status can induce regres sion of such cancers : (a) deprivation of essential hormones ; (b) hormone interference with large amounts of critical compounds.

The earliest indication that regression of advanced The experience with prostatic tumors led to the concept cancer in living creatures can be effected was derived from of hormone dependence and independence. This ter removal of normal organs, namely, the ovaries of women minology (24) was first used in 1945. There is a funda (2). This empiric therapeutic procedure was remarkable mental difference between a normal hormonal target cell insofar as it was made before there was any concept of and its hormone-responsive malignant derivative. In a endocrine action. Following this discovery, Lathrop and normal cell of origin supporting hormones act as catalysts Loeb (32) found that removal of ovaries prevented onset of growth and metabolism, but these compounds are not of mammary cancer in a considerable number of mice. essential for life of the cell. In contrast, a hormone Lacassagne (30) was the first to show that a correlation dependent cancer cell dies when supporting hormones are exists between development of cancer and hormones, withheld or their source is removed. In consequence, a since a steroid with estrogenic activity incited formation cancer cell cannot participate in growth cycles (13) of mammary cancer; in a famous experiment weekly characteristic of the normal cell of origin created by injections of 30 @gof estrone benzoate evoked cancer of alternately administering and withholding supporting the breast in each of 3 male mice in 5â€”6months. hormone. In hormone-dependent cancers of all sorts, The proof that modification of hormonal status can prostatic and others, the supporting hormones are of cause regression of cancer came from a study of tumors of cardinal importance in maintaining the life of the malig canine prostate (15) : injection of stilbestrol resulted in a nant cell. This is the principle of cancer control by hor profound decrease in size of benign and malignant pros mone deprival. tatic tumors, even those of huge size, in the dog. The Cancers can also be controlled by supplying large hormonal control of cancer applied to far advanced amounts of hormones; this is the novel principle (22) of carcinoma of the prostate in man (21). It was found that hormone interference, a pharmacologic concept. Two testosterone accelerated the growth of human prostatic cases where hormone interference kills cancer cells will be cancer, whereas, in contrast, orchiectomy or the injection cited. of estradiol benzoate or of stilbestrol caused in most 1. Heilman and Kendall (10) administered large patients a dramatic and long-lasting regression of their amounts of cortisone to mice bearing a transplanted cancers. Stilbestrol was the first synthetic substance lymphosarcoma: â€œAlthough dramatic and apparently found to be an anti-cancer drug. complete cures are produced, they are only temporary in There are 2 principles in the destruction of cancer cells a majority of the animals.â€• Only lymphomas of adult in living creatures by modifications of endocrine status: male mice failed to be resorbed when cortisone was given, (a), hormone deprival; (b) hormone interference in the and the combined administration of cortisone plus estra cancer cell. Malignant cells can regress from too little or diol-17j3 caused rapid regression of the tumors in these too much hormone. Hormone interference causes severe males. Whereas corticosteroids exerted lethal effects, damage or death of cancer through toxicity in the carwer adrenalectomy does not cause regression of lymphomas in cell while normal cells are relatively undamaged. Not all mice. cancers that regress from hormone deprival also regress Pearson et al. (38, 39) observed that ACTH2 or cortisone from excessive amounts of the same hormones. 2 The following abbreviations are used : ACTH, adrenocortico 1 This investigation was supported by grants from the American tropin; S-D, Sprague-Dawley strain of rats; 3-MC, 3-methyl Cancer Society and the Jane Coffin Childs Memorial Fund for cholanthrene ; 2-AAF, 2-acetaminofluorene; and 7 , 12-DMBA, MedicalResearch. 7,12-dimethylbenz(a)anthracene. 1163

resulted in temporary regression in human lymphatic they give the highest yield of mammary carcinomas in the leukemia and Hodgkin's disease. largest percentage of rats. 2. Huggins et at. (22, 25) induced mammary carcinoma Mammary carcinoma induced by estrogen@.â€”The con in rats, which were then treated for a limited time with tinued exposure to critical doses of estrogens leads to large amounts of estradiol-17fl plus progesterone. This mammary cancer. The method is slow and inefficient, combination of hormones excited such exuberant growth since many months elapse before the tumors appear and of normal mammary cells that the breast resembled that of many of the animals never develop breast cancer (37). rats late 111 pregnancy. Nevertheless, many of the Noble and Collip (36) found that the implantation of niammary cancers were completely extinguished (25), estrone pellets into random-bred hooded rats was followed and 52 % of the rats were free from cancer 6 months after by the development of adenocarcinoma in 28 of 49 rats, steroids were discontinued. Landau et al. (31) found the first tumor appearing after 226 days. Maisin ci &. that â€œacombination of 50 @iig.ofprogesterone and 5 mg. of (34) implanted pellets of stilbestrol in rats that were estradiol benzoate injected intramuscularly and daily, observed for more than 300 days; no mammary cancers induced measurable and clinically worth-while improve arose. We injected 50 @igof estradiol-17fl daily for 400 nient iii 9 of 15 l)atients, including 1 man, with dis.se days in 15 female Sprague-Dawley rats beginning at age 66 nuiiated mammary cancer. Benefit was usually obtained days, the rats earlier having been subjected to ovariec in patients in whom other forms of endocrine therapy tomy-hysterectomy. One rat developed mammary car such as adrenalectomy and oophorectomy had previously cinoma, which was detected after 358 days; 14 rats re promoted tumor regression.â€• Mammary cancer can re mained free from breast cancer. gress from either hormone deprival or hormone inter Mammary carcinoma induced by ionizing radiation.â€” ference from excess of hormones. The selective induction of mammary cancer in the rat by At the present time 7 sorts of cancer are known to be irradiation was discovered by Hamilton (9). A single dose responsive to hormonal modifications of the milieu intÃ©rieur of radioactive isotopes, X-rays, or â€œy-irradiation elicits since shrinkage of cancer and betterment of its host mammary tumors, which arise rather quickly, but in no follow changes in his hormonal status. Cancers of this series have all irradiated rats developed mammary sort are of the breast, prostate, thyroid (1), endometrium cancer. (27), kidney (4, 29), and seminal vesicle (26), and also Hamilton et al. (9) observed a 40 % incidence of mam include lymphoma and leukemia. mary cancer in female S-D rats, aged 55 days, after a In a great many clinical patients, men and women, single injection of 2@At. Maisin et al. (34) found that mammary cancer regresses after any of a considerable some young female rats (strain unspecified) developed number of hormonal modifications. The regression so mammary cancer after total-body irradiation with X induced can be profound and long lasting (6, 11), and, rays. Iii S-D female rats, aged 52 days, given single accordingly, the treatment is of value to the patient. total-body X-irradiation (400 r) and observed for 6 With a single exception (22), all of the procedures found months, mammary carcinomas had the following char to be beneficial for human cancer of the breast were found acteristics (17) : incidence in 29.7 % of the rats; detection directly at the bedside through clinical investigation. of 92 % of the cancers within 79 days; multiple carcinomas The vast aInoulit of work in the laboratory on mammary in 18 % of the rats. In experiments of Cronkite et at. cancer ha@ yielded little that has been applied as therapy (5) 79 % of S-D female rats developed mammary tumors, for women with cancer of the breast. benign and malignant, within 10 months after exposure to Horiiwne-dependent experimental mammary cancer.â€” a single dose of total-body X-irradiation (400 r) and the Spontaneous mammary cancer is common in the dog and 1st tumor was detected 41 days after the exposure. mouse as well as in man. In the dog mammary cancers Shellabarger et at. (43) found that 56 % of female S-D did not shrink after ovariectomy or adrenalectomy (23). rats, aged 40 days, developed mammary tumors after a In various strains of mice possessing the milk agent, single total-body â€˜y-irradiation with a @Coirradiator at sl)oIItaneous mammary cancers of palpable size did not age 40 days. regress following ovariectomy, hypophysectomy, or Mammary carcinoma induced by arornatics.â€”Maisinand administration of testosterone (35). In this regard the Coolen (33) painted the skin of mice repeatedly with a tumors of the dog and mouse differ from many human solution of 3-MO and found, in addition to skin cancer, mammary cancers. It was necessary to find a hormone that carcinoma of the mammary gland arose iIi 18% dependent experimental mammary cancer. of the mice after 7 months. Wilson et at. (47) discovered The key to the solution of this problem was recognition that incorporation of an aromatic (2-AAF) in the diet of of a species with hormone-responsive cancers (14). So rats induced cancer in various tissues; mammary cancer far as is known, the rat is unique among the species arose in a small number of the animals. Shay et at. (42) available for research 011 breast cancer, since only in this observed that the daily intragastric instillation of 3-MO, species are mammary cancers hormone dependent. 2 mg, for many months induced mammary cancer in a Hormone-dependent mammary cancer now can be pro large percentage of Wistar rats; the tumors were detected duced invariably and in potentially unlimited supply with after 129â€”383days. methods of extreme simplicity. We found out (14, 18) that a single large but tolerable There are 3 methods for induction of mammary cancer dose of any of a considerable number of aromatics in the in rats: exposure to (a) estrogens, (b) ionizing radiation, rat consistently induces mammary cancer selectively and and (c) aromatics. Aromatics are the most efficient, since rapidly. Although the conditions for induction are highly

restricted, they are easily satisfied. Eight parameters regard, from a molecular standpoint, 4-aminodiphenyl, have been identified in induction of mammary cancer. consisting of 2 rings, has the simplest structure of the These are (a) the nature and (b) dose of the aromatic; aromatic amines. The least complex of polynuclear (c) species; (d) strain (44) ; (e) age (16) ; and (J) the hor aromatic hydrocarbons, a monomethylbenz(a)anthracene monal status of the rat ; additionally, (g) the animals must (7-methyl- or 12-methyl-), consists of 4 rings. But in remain free from infectious disease and (h) have no con efficiency of dosage, 7 , 12-DMBA exceeds all other tact with cancer-protective substances (20). aromatics by an order of magnitude. In capsule, mammary cancer has always developed in Nature of aromatic-induced tumors in the rat.â€”A single our laboratory in 1500 consecutive female rats of S-D feeding of 7 , 12-DMBA, 20 mg, to 38 female S-D rats, strain, aged 50 days, given a single i.v. injection of a aged 50 days, and observed for 180 days thereafter evoked lipid emulsion, 1 ml, containing 7 , 12-dimethylbenz(a) tumors (25) as follows : mammary cancer, 38 rats ; mam anthracene, 5 mg; the animals were kept in metal cages mary fibroadenoma, 34 rats ; ear duct carcinoma, 2 rats; in an air-conditioned room at 25Â°Â±1Â°C. A single feeding leukemia, 1 rat. Tumors of other structures are less by gastric instifiation of a solution of vegetable oil, 1 ml, common. The tumors occur in 2 discontinuous series: containing 7 , 12-DMBA, 20 mg, can substitute for the mammary carcinoma manifests itself early, and other lipid emulsion. The earliest mammary cancer induced tumors, after 3 months. by this technic was detected by palpation 20 days after All of the mammary cancers evoked by aromatic hydro 7 , 12-DMBA was given. In 90 consecutive rats (12) carbons are rather similar in cytologic appearance, and all mammary cancer was detected in 28â€”92days, mean 42.8 possess the cellular pattern of papillary adenocarcinoma; Â± 11 days. mitoses are abundant. Often in some of the tumors The mammary gland of the young adult S-D female rat islands of squamous carcinoma are present (50) . The stands in the forefront of cells of living creatures in its mammary cancers rarely metastasize but kill the host by susceptibility to induction of cancer. It is equaled only invading muscle and skin, with consequent hemorrhage by cells of certain chickens when they are inoculated with and ulceration. The respiration values (40) are similar a single agent, Rous sarcoma virus I. In a famous experi to those of the normal lactating mammary gland ; the ment of Rous (41), cell-free filtrate of a sarcoma injected high rate of glycolysis, which Warburg (46) found to be into other fowls evoked tumors of palpable size after 10â€” distinctive of the metabolism of cancer, prevailed in the 21 days. induced carcinomas. Dao et al. (8) fed female rats a single dose of 7 , 12-DMBA Young and Oowan (49) found that a number of the and after 4 hr transplanted their mammary glands to induced mammary carcinomas of the rat undergo spon other rats ; mammary cancer arose in the homologous taneous regression. Such tumors have these char recipients of the grafts. acteristics : mammary epithelium remains cubical or Many aromatics share in common the ability to induce columnar; many mitotic figures are present; stroma of the mammary cancer in the rat after a single dose. In this tumor becomes heavily infiltrated with lymphocytes and

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A GE, I III II 11111 II S I II : II I I I I t t t I I I to 20 32 40 50 6470 80 90 100 110 20 30 DAYS CHART 1.â€”The relative effectiveness of hypophysectomy and ovariectomy in extinction of mammary cancer. The age of individual rats at the time of the detection of mammary cancers, which were subsequently found at autopsy, is indicated by â€¢. Mammary cancer found at autopsy is designated an active center. At the age of 32 days, just before the onset of estrus, a lipid emulsion of 7,12-dimethylbenz(a)anthracene (7,12-DMBA), 36 mg/kg, was injected i.v. in Sprague-Dawley female rats. At the age of 64 days, 2 groups of 23 rats were subjected to hypophysectomy or ovariectomy. A group of 23 rats was main tamed intact. Autopsy was performed at the age of 136 days.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. 1166 Cancer Research Vol. 25, August 1965 other mononucleated cells. In our laboratory, we have From the evidence that has been presented it would not observed spontaneous regression of all of the cancers appear that both steroids and protein hormones are of in any rat bearing multiple mammary cancers. It would significance in the maintenance of mammary carcinoma. appear that spontaneous regression is dependent on the REFERENCES quality of the individual tumor and is not a function of 1. Balme, H. W . Metastatic Carcinoma of the Thyroid Success the host's immunologic status. fully Treated with Thyroxine. Lancet, 1: 812â€”13,1954. 1-lorinonal prerequisites for induction of mammary cancer 2. Beatson, G. T. 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Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1965 American Association for Cancer Research. Two Principles in Endocrine Therapy of Cancers: Hormone Deprival and Hormone Interference

Charles Huggins

Cancer Res 1965;25:1163-1167.

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