basis for hormonal management of advanced prostate cancer

1039

Basis for Hormonal Management of Advanced Prostate Cancer Jack Geller, M.D.

Background. In the early 1940s, when it was established that most prostatic cancers were androgen dependent and could be controlled by androgen withdrawal, little was known about the mechanism of androgen action. Measurements of hormones, both in the circulation and in the tissue, were not available, nor were measurements of androgen receptors known at that time.

Since that time, a large body of informa- tion has been published regarding the mechanism of androgen-mediated action. With the understanding of androgen-mediated action has come the opportunity to develop drugs targeted to block specific steps in the sequence of androgen action, beginning in the hypothala- mus-pituitary area and extending down to the intracel- lular processes of enzymatic reduction, receptor binding, and nuclear translocation of the hormone receptor com- plexes. The major focus in prostate cancer therapy currently is the role of the adrenal androgens.

It was established in the 1970s that, after castration, there was a 75% reduction in the dihydrotestosterone (DHT) present in prostate tissue. This observa- tion contrasted with the finding that there was a greater than 90% reduction in circulating testosterone levels in the plasma after castration. Based on this important ob- servation regarding tissue DHT concentrations after castration, attempts were made in the 1980s to block androgen totally using simultaneous gonadal and adrenal sup- pression. Dramatic results were reported after this type of therapy in the early uncontrolled studies. A luteiniz- ing hormone-releasing hormone agonist plus flutamide was used for total androgen blockade. Other techniques for such blockade were available using megestrol acetate in combination with 17-beta-estradiol. One of the key is- sues has been whether the 25% residual DHT after castration provides a sufficient stimulus to growth of residual prostate tumor cells. The best evidence for the importance of the role of adrenal androgens came from clinical studies in which objective clinical responses were found in patients treated with various inhibitors of androgen

Presented at the American Cancer Society National Conference on Prostate Cancer, San Francisco, California, February 13-15, 1992.

From the Department of Medical Education, Mercy Hospital and Medical Center, San Diego, California.

Address for reprints: Jack Geller, M.D., Department of Medical Education, Mercy Hospital and Medical Center, 4077 Fifth Avenue, San Diego, CA 92103-2180.

Methods.

Results.

Accepted for publication August 6, 1992.

action after relapse and castration. If “objectively stable” is included as a category after treatment, then approximately 33% of patients who have relapses after castration can be shown to have an additional response, albeit short, to adrenal androgen withdrawal.

Thus, the control of the relatively small amounts of DHT remaining after castration became a major focus for therapy in metastatic prostate cancer. Cancer 1993; 71:1039-45.

Key words: DHT, testosterone, anti-androgens, prostate cancer, adrenal androgens, flutamide, PSA.

In an epic studies published in 1941, Huggins et al.’ established the concept of androgen dependence of prostate cancer and showed that surgical castration or medical castration with estrogen therapy produced a dramatic reduction in cancer mass and clinical remissions in SO% of patients with advanced metastatic disease. This treatment became the indicated form of therapy for metastatic prostate cancer Stage D1 or D2. Most prostate cancers are metastatic when diagnosed and are either Stage C or D disease. In 1960, it was shown that, not only did dramatic remissions occur after surgical or medical castration in advanced prostate cancer, but also that 5-year survival rates in patients so treated were 20% compared with 0% in placebo or untreated patients.’

Throughout the three decades after the original report, virtually all patients with metastatic prostate cancer were treated with estrogen or surgical castration. Late in the 1960s, a large multicenter Veterans Adminis- tration study was reported, showing that delayed therapy was associated with equally good survival rates as early treatment in metastatic prostate ~ a n c e r . ~ It also established that estrogen, although effective in advanced prostate cancer, had significant cardiovascular and thromboembolic morbidity and mortality rates at the usual dose of 3 mg per day. This report may have provided the impetus to find other effective and less toxic ways of inhibiting androgen-mediated action in metastatic prostate cancer.

During the 1970s, several other significant develop- ments stimulated the development of new strategies for the management of metastatic prostate cancer. It was

Conclusions.

1040 CANCER Supplement February 1, 1993, Volume 71, No. 3

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shown that testosterone was converted rapidly to dihydrotestosterone (DHT), the major biologically active androgen in rat ventral prostate^.^ Others provided a framework to understand the concept of androgen-mediated action at the cell l e ~ e l . ~ - ~ These studies included the development of androgen receptor techniques and the demonstration that an androgen receptor could bind to its ligand with high affinity and low capacity and was able to translocate the receptor-steroid complex into the nucleus of the cell where it was bound to the nuclear DNA and acceptor site. In addition, precise and accurate techniques for measuring picogram amounts of many androgens were developed. At the same time, new antiandrogenic drugs, including both progestational agents, such as cyproterone acetate and megestrol acetate, and pure antiandrogenic drugs, such as flutamide, became available for blocking androgen- mediated action at the cell level.

Thus, a new approach toward understanding and blocking the hormonal factors that were considered important in prostate cancer was born in the 1970s. It was

.

P = 0.33

. * *

-.- - - - - - 1, --.-. 4 *.:: .

shown that although plasma testosterone dramatically decreased by 90% or more after medical or surgical castration, and prostate DHT, the major androgenic stimulus to prostate epithelial cell growth, decreased by only 75% in prostate cancer tissue after castration. These data were reported in the late 1970s and shifted the focus of interest in prostate cancer to the role of adrenal androgens.' As a result of these studies, others developed and publicized the concept of total androgen blockade; in the mid- 1980s, dramatic improvements in time to progression and survival were reported in an uncontrolled clinical study of metastatic prostate cancer using a combination of a gonadotropin-releasing hormone agonist and flutamide to block both gonadal and adrenal androgens." These claims stimulated many other large similar studies, which attempted to dupli- cate these results. Some of these studies are still in prog- ress and will be discussed by other speakers at this sym- posium.

I would like to focus the rest of this discussion on the evidence for the role played by adrenocortical androgens as mediators of androgen action and their possi- ble role in stimulating the growth of prostate cancer. This issue is the crux of a major controversy that exists in this field currently.

The adrenal cortex secretes approximately 4.0 mg/ day of A,-androstenedione, 8.0 mg/day of dehydroepi- androsterone, and 20-30 mg/day of dehydroepiandro- sterone These weak androgens may be converted to testosterone or DHT in peripheral tissues or within the prostate itself.

Conversion of Adrenal Androgens to DHT

There are two reported studies that strongly support the possibility that adrenal androgens may contribute to the concentration of prostate DHT. The first of these studies13 used labeled DHT that could be recovered in prostate tissue from patients who had received tritium- labeled A,-androstenedione or dehydroepiandroste- rone sulfate 0.5 hour before total prostatectomy for be- nign prostate hyperplasia (BPH). The labeled DHT in

I .. - NON- ANDROGEN the p;ostate represented 9% and 2%, respectively, of

the total labeled steroids found in the prostate. Others reported that prostate tissue from 20-25%

of patients who had relapses of prostate cancer after orchiectomy contained levels Of DHT greater than 2.0 ng/g (Fig. l ) . I 4 Such levels of tissue DHT represent sig-

TARGET TLSSUES

N = 13 K 0.933

CASTRATES

N - 37 1 - 1.14

Figure 1. Values for DHT (in nanograms per gram) are shown on the ordinate for whole prostate tissues from patients with prostate cancer who previously were castrated and subsequently required prostate resection. These values are compared with DHT concentrations in various nonandrogen target tissues and demonstrate a subset of seven castrated patients with DHT levels greater than 1.8 ng/g. These levels exceed the DHT values found in any nonandrogen target tissues. Nonandrogen target tissues include the thyroid, intestine, nonsexual skin, gallbladder, and spleen. A P value of 0.33 comparing the two groups was not significant. renal androgens.

nificant accumulations compared with the amounts found in nonandrogen target tissue; these averaged 0.9 ng/g and were always less than 1.8 ng/g. Because these patients who had relapses previously had undergone orchiectomies, the DHT could have come only from ad-

Basis for Hormonal Management/Geller 1041

Effects of Castration and Adrenal Androgen Blockade on Prostate Concentrations of Testosterone and DHT

Prostatic DHT, the major stimulus to prostate cell growth and protein synthesis, decreases in prostate cancer tissue after castration to approximately 25% of basal levels. This is shown in Figure 2. Tissue DHT concentrations average 1.14 ng/g in castrated men with prostate cancer compared with 4.0 ng/g in intact patients with BPH or carcinoma (these groups were pooled because their average DHT values were similar). Megestrol acetate plus either 17-beta-estradiol 1 mg/ day or ketoconazole 1200 mg/day significantly reduces prostate DHT further by partially blocking adrenal androgen secretion in addition to providing a medical castration; finasteride, a 5-alpha-reductase inhibitor, blocks DHT formation almost completely but increases prostate testosterone levels fourfold to fivefold. The de- crease in prostate DHT from values slightly above 1.0 ng/g in castrated men to 0.2 ng/g after finasteride con- firms that adrenal androgens are the source of approximately 25% of prostatic DHT. The key question then is does this relatively small amount of prostatic DHT derived from adrenal androgens have biologic signifi- cance?

The effect of minute amounts of testosterone in- jected into castrated rats was studied.15 It was deter- mined that injecting 1% of the daily secretory rate of testosterone into these rats resulted in significant gains in prostate weight, suggesting that small amounts of

0

Q 6 D H

I

: 4

i 2

T I S

0

P - 0.005 - P - 0.009 *m

ORCH.E(N-37) M+E(N-17) FINASTERIDE(N.10) UNTX(N.137) M.K(N-4)

MEAN VALUE --I STANDARD DEVIATION

Figure 2. On the left, whole tissue DHT concentrations in human prostate tissue are shown for patients with prostate cancer previously treated with orchiectomy with or without 17-beta- estradiol (E). Prostatic DHT levels after megestrol acetate (M, 120 mg/day) plus low-dose E (n = 17) and M (120 &day) plus ketoconazole (K, 1200 mg/day; n = 4) are pooled because they are not significantly different and are shown to the left center. To the right center, are shown patients given 50-100 mg finasteride, and to the far right, are shown untreated control subjects. The standard deviation is shown by "T" bars above each bar, and P values are in brackets.

- - r . . . . . . . . . . . . . I

LOGe (NG D H T l G TISSUE) Figure 3. Correlation between the natural logarithm of tissue DHT (x axis) and the natural logarithm of epithelial protein synthesis (y axis). Circles represent values for tritiated leucine; squares represent natural logarithmic values for sulfate-35-labeled methionine. y = 8.57 + 1 . 2 6 ~ for tritiated leucine: y = 11.89 + 1 . 2 6 ~ for sulfate- 35-labeled methionine. The standard error of the estimate (SEE) = 1.11, rz = 75.4%; t = 4.7 for the coefficient of x with 24 degrees of freedom (df, P < 0,001); t = 7.7 for the difference of intercepts (11.89 - 8.57 = 3.32) with 24 df (P < 0.001). The slopes of separate regressions for tritiated leucine and sulfate-35-labeled methionine do not differ significantly (t = 1.27, 23 df, P = 0.25). Therefore, it is appropriate to combine these two sets of data when an adjustment is made for the different intercepts of the two labels (larger circles and squares illustrate regression lines not actual data points).

androgen may stimulate prostate growth. When the relationship between levels of prostatic DHT and protein synthesis was studied, including both general and specific protein synthesis, it was found that general protein synthesis was estimated by labeled amino acid incorpo- ration into protein by purified epithelial cells that were separated by pronase digestion of surgical specimens obtained from patients with BPH.l6 Inadequate epithelial cell mass was available for DHT assay, and DHT measurements therefore were done on whole tissue from these same prostates. These data are shown in Figure 3. Individual values are plotted as the natural logarithm for both protein synthesis and DHT. Correla- tions between protein synthesis in these separated epithelial cells and DHT concentration in the whole prostate would appear to be valid because the DHT concentration is similar in prostatic epithelium and stroma.17 The upper line represents the regression line for studies done with high specific activity sulfate-35-labeled methionine, and the lower line shows tritiated leucine with a lesser specific activity. The important finding was that the two regression lines were parallel, and the combined data were correlated significantly (P < 0.001) between the DHT concentration and the epithelial cell protein synthesis. These data were derived from studies


of prostates from patients with BPH who were both untreated or treated with varying drug regimens that resulted in a wide spread of DHT values over a 10-fold range. The lowest values were approximately 0.4 ng/g; the highest values were approximately 5.0 ng/g. Be- cause a good correlation could be defined over this large range of DHT, even low values of DHT may regulate prostatic protein synthesis significantly, supporting the possibility that small amounts of DI IT are biologically important in the human prostate.

In more recent studies, we measured both concentrations of DHT and prostate specific antigen (PSA), a unique androgen-dependent prostate protein in the epithelial cell extracts of prostates.” The epithelial cells were obtained by mechanical separation of minced prostates. In 22 studies currently, spanning a wide range of DHT values obtained from both untreated BPH tissue and prostates of patients pretreated with combined androgen blockade, MT found a significant correlation between tissue DHT and PSA concentrations (Fig. 4). Correlation of tissue DHT with PSA levels in the subset of patients treated with combined androgen blockade also showed a significant r value (Fig. 5 ) . This latter study, done in tissues with a low total DHT concentration induced by pharmacologic maneuvers, strongly supported the importance of small amounts of DHT in regulating protein synthesis, at least in regard to one specific protein, PSA. Although these studies support a probable role for DHT in the regulation of human prostatic protein synthesis, they do not address directly the question of DHT and its role in prostate growth.

Response to Adrenal Blockade in Patients in Relapse After Castration

The most compelling evidence for the importance of adrenal androgens as stimuli to prostate tumor growth by conversion to prostatic DHT is the clinical response to adrenal androgen blockade in patients who have had relapses of metastatic prostate cancer after castration. In Table 1, we show that consistent objective responses to various adrenal androgen inhibitors can occur using common criteria defined by the National Prostate Cancer Project.’* In castrated patients who have relapses, flutamide therapy resulted in objective responses in 33% of patients treated by one group.” Others reported a 50% rate of such patients responding to flutamide.” Using megestrol acetate, a high percent- age of castrated patients with relapses became stable objectively after the drug was administered for an average interval of approximately 7 months.” Aminoglu- tethimide therapy resulted in objective clinical responses in 30-40% of a similar group of treated patients.*l.** Finally, there are two reportsz3*’* listed in Table 1 of objective responses to ketoconazole in patients with advanced prostate cancer who had relapses after orchiectomy. Even if we omit patients classified as “objectively stable” and count only those as “partial objective regression” according to National Prostate Cancer Project criteria, there is no doubt that adrenal androgen blockade can produce objective regressions in patients who have relapses after orchiectomy. Others studied clinical responses in 16 patients who had un-

0 - BPH: MA*E

A - CA: YA+E

+ - BPH: NO RX

I - CA: NO RX

0.0 - 0.e -

0.7 -

0.8 - r - 0.662

t - 4.05

0.5 - P < 0.001

0.4 - ui - 0.051

Ao 0 0 0 1 1 . 1 1 I I 1 I I 1 1 1 I I 1

0 2 4 6 8 10 12 I4 18 (Thouaands)

n( PSWmg DNA TOTAL RAN08 -

Figure 4. This figure shows a significant correlation between U t i T and I’SA in 22 mechanically separated epithelial cell homogenatcs from prostates of both treated and untreated patients (no treatment) with BPI1 and prostate cancer. In the legend, MA t E = megestrol acetate 160 mg/day and cstradiol 1.0 mg/ day. The therapeutic interval in the one patient with treated prostate

~ cancer was 18 months. Otherwise, 1 treatment was givcn for 1 wcck

before tissue removal. The r value for the correlation bctwccn D€IT and PSA was 0.662 ( P < 0.001).

Basis for Hormonal Management/GelZer 1043

300

280 - 200 - 240 - Figure 5, This figure is similar to

patients treated with megestrol acetate 160 mg/day plus estradiol 1 0 mg/day (MA + E) for 1 week before prostate surgery. Notice the much lower scale for picograms of DHT per milligrams of DNA on the

Figure 4. There is a significant correlation between DHT and PSA

8 0 -

0 0 - epithelial extracts derived by mechanical separation of BPH tissues from nine patients treated with MA 40 -

20 - + E The r value for these nine data points is 0.946 (P < 0.002). The

Figure 4 but shows data for the nine 220 - 200 - 180 - Id0 - 140 -

P +

r - 0.Y46

t - 4.87

P ( 0.002

2 100 - m - 0.040

E' \

ordinate compared with that in P 120 -

levels in the human prostate

least-squares regression line of the 0 1 t i 1 1

data points has a slope of 0.040. Each data point for DHT and PSA is represented by +.

0 2 4 (Thousand#)

n( PSA/m( DNA mAtL - TRUATBD RANCB

dergone adrenale~tomies.~~ Although this study was done before the National Prostate Cancer Project criteria were established, four patients with advanced disease survived longer 12 months, suggesting a favorable

effect of surgical adrenalectomy in a subset of 25% of patients. The data therefore are compelling that blockade of adrenal androgens, either at the level of the adrenal cortex or at the prostate itself, may arrest prostate

Table 1. Clinical Effects of Adrenal Androgen Blockade in Patients With Stage D2 Prostate Cancer Who Have Had a Relapse After Castration

Drug author (no. of cases)

Mean duration Initial response rate Criteria for of response remonse Obiective Subjective or survival

Flutamide DiSilverio (20) NPCP 50% Labrie et al. (209) NPCP 34.546 overall

6.2% CR

18.6% 0 s 9.6% POR

Megestrol acetate Geller (11) NPCP

Aminoglu tethimide Drago et al. (43) NPCP Murray (126) NPCP

8196 (940 POR) (72% 0 s )

Ketoconazole Murray (78) NPCP 31% Williams (20) BPGC 30% 5096

Not specified Mean survival

> 2.5 yr

7 mo response

6-42 mo response 10 mo response

(some patients still responding)

BPGC: British Prostate Group Consortium; NPCP: National Prostate Cancer Project; CR: complete objective regression, POR: partial objective regression; 0 s : obiectively stable.


cancer growth temporarily and may cause a disease remission in a subset of 33% of patients who have had relapses after castration.

Discussion

There is no doubt that adrenal androgens are a source of prostatic DHT and explain approximately 25% of the DHT present in the average prostate. Nevertheless, this small amount of adrenal-derived DHT appears to be biologically active and important (Figs. 3 and 4 and Ta- ble 1).

Recently, the relationship was studied between various levels of tissue DHT and prostate cell number in intact, castrated, and castrated plus adrenalectomized rats.26 There was no change in prostate cell number in castrated plus adrenalectomized rats compared with rats who were castrated only, despite the finding that prostatic DHT concentrations were lowered significantly by removal of both androgen sources compared with the removal of the gonads alone. The authors in- terpreted this to be a quanta1 response, indicating a threshold for the effect of DHT on the cell number; such an effect occurred after castration alone. This rat study suggests that prostatic DHT derived from the adrenal is not biologically important.

A criticism of this article was that virtually no androgens are secreted by rat adrenal glands. If this is true, we question the changes in DHT concentration after adrenalectomy reported in that article and whether the growth data were really relevant. Another recent report2’ also denied the importance of small amounts of androgen in the growth of prostate PC-82 tumors grown in nude mice. However, administration of the lowest dose of testosterone used in this study, shown in Figure 2 of their article, significantly stimulated tumor growth in castrated nude mice compared with placebo-treated mice.

Additional support for a biologically important role for adrenal androgens came from objective responses that occurred in approximately 33% of patients treated with various drugs to block adrenal androgens in patients who have had relapses after castration (Table l). A subset of patients also appeared to show a favorable response to surgical adrenale~tomy.’~ Remissions induced by blockade of the adrenal androgens generally are short. Based on the data in Table 1, we might expect a 6-10-month longer time to progression in approximately 33% of patients who are treated initially for their metastatic prostate cancer with combined androgen blockade compared with castration alone. The large Southwest Oncology Group trial indicated that a 2.6- month significant increase in median time to progres-

sion and a 7.3-month significant median time to survival occurred with combined androgen blockade.28 This fits well with the possibility that 33% of patients may experience 6 additional months of remission with combined androgen blockade because such a response would average approximately 2 months if, in the group as a whole, two of three patients had no response (response rate similar to adrenal androgen blockade in castrated men with relapses).

What appears to characterize this subset of 33% of patients whose tumor growth is responsive to prostatic DHT derived from adrenal androgen? No tissue or blood markers have been identified currently; heteroge- neous tumor cells may include a significant population that are hormone sensitive in addition to those that are hormone dependent. Such cells may survive without androgen but grow more rapidly in the presence of even small amounts of DHT, such as the level derived from adrenal androgens, whereas hormone-dependent cells regress or die when androgen is decreased drasti- cally by ~ a s t r a t i o n . ~ ~ Another possibility is that the conversion of adrenal androgens to DHT in the prostate is greater in the 33% of patients who respond to blockade of adrenal androgens than in nonresponders. In previously reported data, we found that prostatic DHT concentration in 25% of patients with prostate cancer who had been castrated previously was higher than the concentrations found in nonandrogen target tissues in untreated patients, suggesting a role for adrenal androgen contribution to DHT in some of the castrated men (Fig. 1).

Summary

Testosterone from the gonads is the major source of DHT in the prostate. However, adrenocortical androgens also may be converted into DHT in the prostate and provide approximately 25% of the DHT present in that organ. Biochemical studies in human BPH tissue and clinical responses to blockade of adrenal androgens in castrated men support a biologically significant role for adrenal androgens in stimulating protein synthesis in prostate tissue. Contrary conclusions in animal mod- els have been reported, and there is therefore no con- sensus currently in regard to this matter. This issue must continue to be studied because it constitutes the basis for appropriate hormonal therapy in prostate cancer.

References

1. Huggins C, Hodges CV. Studies on prostatic cancer: I. Effect of castration, of estrogen and of androgen injections on serum

Basis for Hormonal Management/GeZler 1045

2

3

4

5

6

7

8

9

10

11

12

13

14

15

phosphatases in metastatic carcinoma of the prostate. Cancer Res

Emmett JL, Greene LF, Papantoniou A. Endocrine therapy in carcinoma of the prostate gland: 10-year survival studies. J Urol

Veterans Administration Cooperative Urological Research Group. Treatment and survival of patients with cancer of the prostate. S l u g Gytiecol Obstet 1967; 124:lOll-7. Bruchovsky N, Wilson JD. The conversion of testosterone to 5-a androstan 17-ol-3-one by rat prostate in vivo and in vitro. J Biol Cheni 1968; 243;2012-21. Liao S. Biochemical studies on the receptor mechanisms in- volved in androgen actions. In: Richenberg HV, editor. MTP international review of science, biochemistry of hormones. vol. 8. London: Butterworth, 1974:154-85. Fang S, Liao S. Androgen receptors: steroid and tissue specific retention of a 17-0 hydroxy 5a-androstan-3 one-protein complex by the cell nuclei of ventral prostate. j Biol Chetii 1971; 246: 16-24. Tymoczko JL, Liao S. Retention of an androgen protein complex by nuclear chromatin aggregates: heat labile factors. Biochini Biophys Ar ta 1971; 252:607-11. Liao S, Liang T, Tymoczko JL. Structural recognitions in the interactions of androgens and receptor proteins and in their asso- ciation with nuclear acceptor components. j Steroid Biorhetn Mol

Geller J , Albert J, Loza D, Geller S, Stoeltzing W. DHT concentrations in human prostate cancer tissue. J CIiti Endocriiiol Mr tab

Labrie F, Dupont A, Belanger A. LHRH agonists and antiandro- gensin prostate cancer. In: Ratliff TL, Catalona WJ, editors. Geni- tourinary cancer. Boston: Martinus Nijhoff, 1987:157-200. Baird DT, Uno A, Melbe JC. Adrenal secretion of androgens and estrogens. ] Etidocrinol 1969; 45:135-6. Sanford EJ, Poulson DF, Rohner DJ, Drago JR, Santen RJ, Bardin CW. The effects of castration on adrenal testosterone secretion in men with prostatic carcinoma. j Urol 1977; 118:1019-21. Harper ME, Pike A, Peeling WB, Griffiths K. Steroids of adrenal origin metabolized by human prostatic tissue both in vivo and in vitro. ] Endocritiol 1974; 60:117-25. Geller J, Albert ID, Nachtsheim DA, Loza D. Comparison of prostate cancer tissue dihydrotestosterone levels at the time of relapse following orchiectomy or estrogen therapy. J Urol 1984; 132:693-6. Bartsch W, Knabbe C, Voight KD. Regulation and compartmen- talization of androgens in rat prostate and muscle. ]Steroid Bio- rhem Mol Biol 1987; 19:929-37.

1941; 1:293-7.

1960; 83:471-84.

Biol 1972; 3:401-8.

1978; 46~440-4.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

Geller J, Liu J, Albert J, Fay W, Berry CC, Weis P. Relationship between human prostate epithelial cell protein synthesis and tissue dihydrotestosterone level. Cliti Etzdocritzol 1987; 26:155- 61. Bruchovsky N, McLoughlin MG, Rennie PS, To MP. Partial char- acterization of stromal and epithelial forms of five alpha reductase in human prostate, the prostatic cell: structure and function. part A. New York: Alan R. Liss, 1981:161-75. Schmidt JD, Gibbons RP, Johnson DE. Chemotherapy of advanced prostatic cancer: evaluation of response parameters. Urology 1976; 7:602-10. DiSilverio F, Tenaglia R, Ferraro F, DEramo G, Petrangeli E. Use of flutamide in treatment of prostate cancer [abstract]. j Steroid Biochern Mol Biol 1985; 23:40S. Geller J, Albert J, Yen SSC. Treatment of advanced cancer of the prostate with megestrol acetate. Urology 1978; 12:537-41. Drago JR, Santen RJ, Lipton A, Worgul TJ, Harvey HA, Boucher A, et al. Clinical effect of aminoglutethimide medical adrenalectomy in treatment of 43 patients with advanced prostatic carcinoma. Caticer 1984; 53:1446-50. Murray R, Pitt P. Treatment of advanced prostatic cancer, resis- tant to conventional therapy, with aminoglutethimide. Eur ] Cancer 1985; 21:453-8. Murray R, Pitt P. Adrenal blockade with aminoglutethimide in prostate cancer [abstract]. Urol Res 1986; 3:65. Williams G, Kerle DJ, Ware A, et al. Objective responses to ketoconazole therapy in patients with relapsed progressive prostate cancer. B r j Urol 1986; 58:45-51. Bhanalaph T, Varkarakis MJ, Murphy GP. Current status of bilat- eral adrenalectomy of advanced prostatic carcinoma. Anti Siirg

Kyprianou N, Isaacs JT. Quanta1 relationship between prostatic dihydrotestosterone and prostatic cell contact: critical threshold concept. Prostate 1987; 11:41-50. Van Weerden WM, Van Steenbrugge GJ, Van Kreuningen A, Moerings EPCM, De Jong FH, Schroder FH. Assessment of the critical level of androgen for growth response of translatable human prostatic carcinoma (PC-82) in nude mice. ] Urol 1991; 145:631-4. Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Ben- son R, Dorr FA, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Etigl ] Mrd 1989;

Bruchovsky N, Lesser B. Control of proliferative growth in androgen responsive organs and neoplasms: cellular mechanisms modulating gonadal hormone action. In: Singhal RL, Thomas JA, editors. Advances in sex hormone research. vol. 2. Baltimore: University Park Press, 1975:l-55.

1974; 179:17-23.

321 ~419-24.

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