Cancer Res 1941 Huggins 293 7

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S t u d i e s o n P r o s t a t i c a n c e r

I . The E f fec t o f Cas t r a t i on , o f Es t rogen and o f A ndrogen

I n je c ti on o n S e r u m P h o s p h a t a s e s in M e t a s t a t i c

C a r c i n o m a o f t h e P r o s t a t e

Charles Huggins M .D. and Clarence V. Hodges M .D.

From the Department o] Surgery, the University o] Chicago, Chicago, Illinois)

(Received for publication M arch 22, I94 I)

C a r c i n o m a o f t h e p r o s t a t e g l a n d i s p e c u l i a r l y f a v o r-

a b l e f o r e n d o c r i n e i n v e s t i g a t i o n s i n c e f r e q u e n t s e r i a l

o b s e r v a t io n s o f t h e a c t i v it y o f p h o s p h a t a s e s i n s e r u m

w e r e f o u n d t o p r o v i d e o b j e c t iv e i n d i c e s o f a c ti v i t y o f

t h e n e o p l a s m w h e n t h e e n z y m e s w e r e i n c r e a s e d i n

a m o u n t a b o v e n o r m a l . I n t h e p r e s e n t p a p e r d a t a a re

g i v e n f o r t h e v a l u e s o f s e r u m p h o s p h a t a s e s i n c a r -

c i n o m a o f t h e p r o s t a t e a n d i n n o r m a l m e n . W e s h a l l

d e m o n s t r a t e t h a t t h e a c id p h o s p h a t a s e o f s e r u m i s

r e d u c e d i n m e t a s t a t i c c a r c i n o m a o f t h e p r o s t a t e b y d e -

c r e a s i n g t h e a c ti v i t y o f a n d r o g e n s t h r o u g h c a s t r a t i o n

o r e s t r o g e n i c i n je c t i o n s a n d t h a t t h i s e n z y m e i s i n -

c r ea s ed b y i n j e c ti n g a n d r o g e n s . W e h a v e b e e n u n a b l e

t o f i n d p r e v i o u s o b s e r v a t i o n s i n d i c a t i n g a n y r e l a t i o n -

s h i p o f h o r m o n e s t o c a r c i n o m a o f t h e p r o s t a t e g l a n d .

An enzyme capable of h ydrolyzing phosphoric e s ters was

discovered by Grosser and H usler (4) in intestinal muc osa and

kidney. Rob ison (I6 ) found that this enzyme was particularly

high in activity in grow ing bo ne and cartilage and that its ac-

tivity was greatest at pH 9 to 9.5- Th is alkaline phospha-

tase was found by Kay (9) to be increased in the serum

in certain b on e diseases including m etastasis of n eop lasm s to

bone and later work has shown that among these condi tions

is carcinoma of the prostate.

Davies (3) and Bamann and Rie del ( I ) discovered that

there occurs in the splee n and kidne y 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 identi-

cal with this acid phosphatase was found by Kutscher and

Wo lbergs (I I) to be present in very large amo unt in the

hum an pros tate gland. This finding of great activity of acid

phosphatase in the prostate gland was confirmed and extended

to include prostatic cancer by Gutrnan, Sp roul, and G utma n (7).

The serum of certain patients with disseminated prostatic

carcinoma was found by Gutman and Gutman (6) and Bar-

ringer and Woodard (2) to exhibit increased acid phosphatase

activity. Robinson, Gutm an, and Gutm an (I5 ) sum marized the

acid phosphatase activity levels of 44 pa tients with carcinoma of

the prostate. They concluded that a marked r ise in acid phos-

phatase in serum is associated with the appe aranc e or sp read

of roentgenologically demonstrable skeletal metastases and im-

plies dissemination of the primary tumor and thus is of un-

favorable prognostic significance.

* This investigation w as aided by a gran t from the C om-

mittee on Research in Prob lems of Sex , the National Research

Council.

M E T H O D S N D M T E R I L S

T h e p h o s p h a t a s e a c t iv i t y o f s e ru m w a s d e t e r m i n e d

b y t h e m e t h o d o f K i n g a n d A r m s t r o n g ( i o ) u s i n g

0 .0 0 5 M d i s o d i u m m o n o p h e n y l p h o s p h a t e a s su b s tr a te .

T h e b u f f e r s u s e d w e r e 0 . 0 5 M b a r b i t a l - s o d i u m a t

p H 9 . 3, a n d o . i M S 6 r e n s e n ' s c i t r a te - H C 1 o r W a l p o l e ' s

0 .2 N s o d i u m a c e t a te - a c e ti c a c i d b u f fe r s a t p H 5 - A l l

s e r u m s w e r e t e s t e d i n d u p l i c a t e a n d w e r e a d d e d

d i r e c t l y t o b u f f e r - s u b s t r a t e s o l u t i o n s w i t h o u t d i l u t i o n ;

t h e y w e r e i n c u b a t e d a t 3 7 . 5 ~ C . f o r 3 ~ m i n u t e s . P r e -

c a u t i o n s w e r e o b s e r v e d t h a t a l l s o l u t i o n s w e r e a t t h i s

t e m p e r a t u r e b e f o re t e st in g . B l a n k s w e r e r u n b y a d d -

i n g t h e p r o t e i n p r e c i p i t a n t t o t h e b u f f e r - s u b s t r a t e s o l u -

t i o n b e f o re a d d i n g s e r u m . C o l o r i m e t r i c p r o c e d u r e s

w e r e c a r r i e d o u t w i t h t h e E v e l y n p h o t o e l e c t r i c c o l o r -

i m e t e r u s i n g a 6 6 0 0 A f i lt e r . T he r e s u l t s a r e exp r e s s ed

i n K i n g a n d A r m s t r o n g u n i t s , a u n i t b e i n g d e f i n e d a s

t h a t d e g r e e o f p h o s p h a t a s e a c t i v i ty w h i c h a t p H 9 .3

( o r p H 5 . 0, r e s p e c t i v e l y ) a n d 3 7 .5 ~ C . w i l l l i b e r a t e

i m g m . o f p h e n o l f r o m t h e s p e c i fi e d b u f fe r - s u b s t r a te

s o l u t i o n i n o n e - h a l f h o u r .

P h o s p h a t a s e d e t e r m i n a t i o n s a t p H 5 a n d 9 . 3 w e r e

m a d e o n t h e s e r u m o f 4 ~ n o r m a l m e n , o f 2 I m e n w i t h

b e n i g n p r o s t a ti c h y p e r t r o p h y , a n d o f 4 7 m e n w i t h c a r -

c i n o m a o f t h e p r o s t a t e . T h e d i a g n o s i s o f c a r c i n o m a o f

t h e p r o s t a t e g l a n d w a s d e r i v e d f r o m o n e o r m o r e

o f t h e f o l l o w i n g p r o c e d u r e s : r e c t a l p a l p a t i o n , c y s t o -

s c o p i c e x a m i n a t i o n , t r a n s u r e t h r a l r e s e c t i o n w i t h m i c r o -

s c o p i c e x a m i n a t i o n , o r r o e n t g e n o l o g i c e v i d e n c e o f

s k e l e t a l m e t a s t a s e s. N e c r o p s y w a s o b t a i n e d i n 2 c a se s .

A l l p a t i e n t s h a d x - r a y s t u d i e s o f t h e b o n y p e l v i s .

E i g h t p a t i e n t s w h o h a d c a r c i n o m a o f t h e p r o s t a t e

w i t h s k e le t a l m e t a s ta s e s a n d w i t h m o d e r a t e o r g r e a t

e l e v a t i o n o f a c i d p h o s p h a t a s e o f s e r u m v a l u e s a b o v e

2 0 u n i t s i n I o o c c . w e r e s e l e ct e d f o r i n t e n s i v e s t u d y i n

t h e h o s p i ta l . E a c h p a t i e n t a ls o h a d e l e v a t i o n o f a l k a -

l i n e p h o s p h a t a s e i n t h e se r u m . B o t h o f th e s e e n z y m e s

w e r e d e t e r m i n e d o n t h e s e r u m 3 t i m e s w e e k l y f o r

m a n y w e e k s . B i l a t e r a l c a s t r a t i o n w a s c a r r i e d o u t i n

a l l. F i v e p a t i e n t s w e r e i n j e c t e d w i t h s t il b e s tr o l , i m g m .

293

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294

C a n c e r R e s e a r c h

daily, or estradiol benzoate, x.66 to 3.32 mgm. daily,

before castration. Thr ee patients were injected with

testosterone propionate, 1 25 mgm . daily, in sesame oil.

The phosphatases of cerebrospinal fluid in 3 cases

and of spermatocele fluid in I case were determined

concurrently with those of the serum on x occasion.

I n t h i s paper un i t s o / e n zy m e re / e r t o IOO CC O/ t he

speci f ied body f luid.

In 4 normal adult male dogs, serial observations of

the phosphatases of the serum were made during I

week before and 4 weeks after bilateral castration.

Castration was done under ether anesthesia.

60

50

40

C

CID

20

I

: y ~ :

UNITS I0 ZO

LK LINE

30 40 50 60 70 BO

F IG . I . - - S c a t t e r d i a g r a m o f ac i d a n d a l k a l i n e p h o s p h a t a s e

v a l u e s in s e r u m i n c a r c i n o m a o f t h e p r o s t at e . O r d i n a t e s , a c i d

p h o s p h a t a s e ; a b s c i s s a e , a l k a l i n e p h o s p h a t a s e .

R E S U L T S

V al ues i n carc i noma o / t he pros t a t e and i n con t ro l s .

The values with standard deviation in the control

groups were: in the serum of 4 o normal m en, acid

phosphatase 3.25-+-i.37 units, alkaline phosphatase

8.I5___ 1.74 units. Th e upp er limi t for aci d phospha -

tase is slightly higher than that of Gutman and Gut-

man 6) who used citrate buffer, whereas most of our

determinations were made with acetate buffering. The

nature os the buffer is not the cause of the difference

obtained, however, since determinations made in paral-

lel using citrate and acetate buffer yielded identical

results.

The values in 47 cases of carcinoma of the prostate

with and without demonstrable metastases are shown

in Fig. i. Of these 47 patients, 23 had acid phosphatase

below 4-5 units and alkaline phosph atase below i2. 5

units; of the remaining 24 patients all had elevation

1 T h e a u t h o r s a r e i n d e b t e d t o D r . E r w i n S c h w e n k a n d t h e

S c h e r i n g C o r p o r a t i o n f o r g e n e r o u s d o n a t i o n s o f e s t r a d i o l b e n -

z o a t e a n d t e s t o s te r o n e p r o p i o n a t e a n d t o D r . J . A . M o r r e l l o f

E . R . S q u i b b S o n s f o r t h e s t i l b e s t r o l u s e d .

of alkaline phosphatase above 12. 5 units, and 2i had

acid phosphatase values above 5 units.

C orre l a t i on be t w een roen t geno l og i c ev i dence o f

ske l e t a l me t as t ases and serum phospha t ases . - - P os i t i ve

x-ray evidence of metastasis of prostatic carcinoma to

the bo ny pelvis was obtain ed in 25 cases. Both acid

and alkaline phosphatase activities of the serum were

increased above normal in 19 cases. Alkaline phos-

phatase alone was increased in 2 cases while acid

phosphatase was within normal limits, and neither

enz yme was increased in 4 cases. The re was no

evidence of metastasis on x-ray examination of the

pelvis of 2o patients; in i6 men both acid and alkaline

phosphatase were normal; in 3 men alkaline phos-

phatase was elevated but in none of this group was

the acid phosphatase increased in amou nt. No deduc-

tions could be made from enzyme study of the serum

with respect to the osteoplastic or osteolytic nature of

the metastatic lesion.

E l yec t o / cas t ra t i on . A c i d phosp ha t ase . - - I n

each of

8 patients with prostatic cancer this activity rapidly

decreased following bilateral orchiectomy.

Following operation, in the case of P. R., there was a fall from

26 to 5 units in 7 days Fig. 2); in the case of J. R. a

decrease from 35 to 3 units in 9 days Fig. 3); in the case

of O. A. there was a fall from 25 to 5 units in I2 days; in

the case of C. B. a decrease from 39 to 9 units in I2 days.

Following castration the decrease usually persisted

in a range slightly above or below the upper limits of

the normal values; it was maintained at this value

with slight fluctuation during the period of observation

which in the longest case has been i8o days.

The values observed in the case of P. R. varied from 2.5

to 7.5 units during I5o days; in the case of J. R. between 3

and 6 units in xo4 days; in the case of C. B. between 7 and 9

units in I25 days; and in M. M. the values fluctuated between

9 and I5 units per ioo cc. in i8o days.

In one patient, S. R., ac id and alkaline phosphatase levels of

serum were 9o and 3o units respectively i63 days aft er orchi-

ectomy. No other enzyme studies were made on this man, who

was the only patien with high enzyme levels after orchiectomy.

In one patient, J. F., with benign prostatic hypertrophy who

was subjected to castration, as previously reported by Huggins

and Stevens 8), acid and alkaline serum phosphatases were

3 and 9.25 units, respectively, 2 years after orchiectomy.

In 4 dogs, the values of the serum phosphatases were

within the range found in normal men; bilateral

orchiectomy resulted in no essential changes in their

levels.

A l k a l i n e p h o s p h a t a s e . N A

rise was always observed

in the value of this enzyme following castration in this

series of patients. This rise was the n succeeded by a

decrease to or towards the normal value.

I n t h e c a s e o f J . R ., t h e v a l u e a t t h e t i m e o f c a s t r a t i o n w a s 1 9

u n i t s . T h e m a x i m u m v a l u e , 4 1 u n i ts , w a s a t t a in e d 3 9 c la ys fo l -

l o w i n g o r c h i e c t o m y , a n d a t l O 4 d a y s t h e v a l u e w a s 2 o u n i t s .

I n t h e c a s e o f P . R . t h e p r e c a s t r a t i o n v a l u e w a s 2 2 u n i t s , t h e

m a x i m u m v a l u e f o u n d w a s 2 7 u n i t s I O d a y s a f t e r c a s t ra t i o n , a n d






H u ggi n s et al . Seru m Ph osphatase an d Prostat ic Cancer 95

th i s value decre ased to 9 uni t s a t 15o days . In the case of

C . B . t h e p r ecas t r a t i o n v a l u e w as 8 2 u n it s , t h e m ax i m u m r i se

t o 9 4 u n i t s w as s een 1 2 d ay s fo l l o w i n g o r ch i ec t o m y , an d t h e

l a s t v a l u e o b t a i n ed w as 3 5 u n i t s 1 2 5 d ay s fo l l o w i n g t e s t i s

r em o v a l .

Effect o/ estrogen inject ion. Estrogen w a s g i v e n

d u r i n g p e r i o d s o f 8 t o 2 3 d a y s ; a ll p a t i e n ts d e v e l o p e d

s m a l l p a l p a b l e a r e a s o f s u b a r e o l a r b r e a s t t i s su e . T h e

r e s u lt s w e r e s i m i l a r t o t h o s e o b s e r v e d f o l l o w i n g c a s t ra -

t io n ; n a m e l y , a s h a r p d e c r e a s e o f a c id p h o s p h a t a s e

Effect o/ androgen inject ion. Testosterone p r o p i o -

n a t e c a u s e d a n in c r e a s e o f s e r u m a c i d p h o s p h a t a s e

a b o v e t h e p r e - i n j e c t i o n l e v e l i n th e s e p a t ie n t s . F o l l o w -

i n g t h e c e s s a t i o n o f i n j e c t i o n s , t h e r e w a s a d e c l i n e t o

t h e p r e l i m i n a r y l e v el . I n o n e p a t i e n t t hi s d e c r e a s e w a s

s u c c e e d e d b y a m a r k e d i n c r e a s e i n a c i d p h o s p h a t a s e .

T h e r e w e r e n o c h a n g e s i n a l k a l in e p h o s p h a t a s e d u r i n g

t h e p e r i o d o f i n je c t i o n , b u t a r i se o c c u r r e d s u b s e q u e n t

t o t r e a t m e n t .

dNITS

25

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UNITS I I ' ' ' 3

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BILATERAL ORCHIECTOMY

l~~ .... .. ~176 .

p ... ... ..._._,...

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I i I I I - - . I I

7 io 0AY5 2.0 30 4.0 50

5 T I L B E S T R O L - I M G . D A I L Y

I I I

4 5 D A Y S 6 7 8

U N I T S

6 0

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4 0

3 0

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I I I I

TESTOSTERONER O P I O N A T [ 2 5 M ~ALLY ]

T O T A L 4 5 0 M G .

I I I I

1 0 2 0 D A Y S 3 0 4 0

F 1 o. 2 . - - T h e e f f ec t o f ca s tr a t i o n o n s e ru m p h o s p h a t a s es i n m e t a s t a t i c ca r c i n o m a o f t h e p ro s t a te i n t h e ca s e o f P . R . A c i d

p h o s p h a t a s e ; a l k a l i n e p h o s p h a t a s e - - .

F i o . 3 . - -T h e e f f ec t o f ca s t r a ti o n o n s e ru m p h o s p h a t a s e v a l u es i n m e t a s t a t i c ca r c i n o m a o f t h e p ro s t a t e i n t h e ca s e o ~

J . R . A c i d p h o s p h a t a s e , a l k a l i n e p h o s p h a t a s e

F ro . 4 . - - -T h e e f f ec t o f e s t ro g en i n jec t i o n , I m g m . s t i l b e s tro l f o r 23 d ay s , o n s e ru m p h o s p h a t a s es i n m e t a s t a t i c ca r c i n o m a

o f t h e p ro s t a t e i n t h e ca s e o f O . A . A c i d p h o s p h a t a s e ; a l k a l i n e p h o s p h a t a s e . O rd i n a t e s , u n i t s p e r IOO cc .

o f s e ru m ; ab s c i s s ae , t i m e i n d ay s .

F ro . 5 . - - -T h e e f f ec t o f an d ro g en i n j ec t io n , t e s t o s t e ro n e p ro p i o n a t e , 2 5 m g m . d a i l y fo r x 8 d ay s , o n s e ru m p h o s p h a t a s es

i n m e t a s t a t i c ca r c i n o m a o f t h e p ro s t a t e i n t h e ca s e o f O . A . A c i d p h o s p h a t a s e ; a l k a l i n e p h o s p h a t a s e . . . . .

a c c o m p a n i e d b y a n in c r e a s e o f a l k a l i n e p h o s p h a t a s e i n

t h e s e r u m .

T h e p a t i en t P . M . w as i n j ec t ed w i t h 7 m g m . s t i l b e s t ro l

an d 4 6 . 5 m g m . e s t r ad i o l b en zo a t e i n 2 7 d ay s . T h e ac i d p h o s -

p h a t a s e o f h i s s e ru m d ec reas ed f ro m 5 o t o 1 9 . 5 u n i t s w h i l e

t h e a l k a li n e p h o s p h a t a s e ro s e f ro m 5 5 t o 95 . 5 u n i t s. J . C .

r ece i v ed 8 m g m . s t il b e s tro l i n 8 d ay s . H i s ac i d p h o s p h a t a s e

f e l l f r o m 3 2 t o 4 -5 u n i t s w h i l e t h e a l k a l i n e p h o s p h a t a s e ro s e

from 27.5 to 64 .5 uni t s . O. A. received 3 ~ mgm . s t i lbes t ro l in

2 3 d ay s F i g . 4 ) . A c i d p h o s p h a t a s e o f h i s s e ru m d ec reas ed

f ro m 4 8 t o 4 -5 u n i t s w h i l e a l k a l i n e p h o s p h a t a s e i n c r eas ed f ro m

23 to 41 .5 uni t s .

I n t h e ca s e o f C . B . , p r ev i o u s l y ca s t r a t ed , i n j ec t ed w i t h 2 5

m g rn . t e s t o s t e ro n e p ro p i o n a t e d a i l y fo r 1 5 d ay s , ac i d p h o s p h a -

t a s e ro s e f ro m 9 t o 2 7 u n i ts ; c e s s a t i o n o f an d ro g en i n j ec t i o n w as

fo l l o w ed b y a d ec reas e t o 9 u n i t s 9 d ay s fo l l o w i n g i n j ec t i o n .

In t h e ca s e o f O . A . , i n j ec ted w i t h 2 5 m g m . t e s t o s t e ro n e p ro -

p i o n a t e d a i l y fo r 18 d ay s , ac i d p h o s p h a t a s e ro s e f ro m I I u n i t s

t o a h i g h v a l u e o f 4 8 . 7 5 u n i t s r each ed t h e d a y fo l l o w i n g co m p l e -

t i o n o f an d ro g e n i n j ec t i o n . T h i s v a l u e d ec reas ed t o 2 3 .5 u n i t s

6 d ay s fo l l o w i n g ces s a t i o n o f an d ro g en s , w h e reu p o n i t r o s e t o

4 6 u n i ts i n t h e n ex t 2 7 d ay s F i g . 5 ) .

Distribution o[ phosph atases in body fluid s in car

c inoma o / t he pros ta t e . The p h o s p h a t a s e s w e r e f o u n d






2 9 6 ancer Research

t o be l ow in ce r eb rosp ina l f l u id and i n spe rm a toce l e

f l u i d a l t h o u g h t h e v a l u e s w e r e c o n c u r r e n t l y h i g h i n

b l o o d s e r u m .

In the ca se of P. M., acid and a lkalin e phosphatases of the

spinal fluid were 0.75 and o un its at a t ime wh en these enzymes

in the seru m were 5I and 64 units respectively. Similarly in

O. A. , acid and alkaline phosphatases of s pinal fluid were

o and o at a t ime whe n the findings in se rum were 23 and

22 u nit s respectively. In the case of J. C., ac id and alkaline

phosphatases of spinal fluid were o and 1.5 units w hen these

levels in se rum wer e I9.5 and 46 un its respectively. In the

case of C . R., acid and alkalin e phosphatases of spermatocele

fluid were o and 1.5 when the seru m levels wer e 49 and 62

units, respectively.

DISCUSSION

I n d i s s e m i n a t e d c a r c i n o m a o f t h e p r o s t a t e t h e

l ab i l i t y o f a c id phospha t a se i n s e rum as i n f l uenced by

a n d r o g e n s u p p l y o r w i t h d r a w a l i n d i c a t e s t h a t t h i s

m a l ignancy i s i n f l uenced by t he ac t i v i t y o f m a l e ho r -

m o n e s i n t h e h o st . W i t h r e sp e c t t o s e r u m e n z y m e s ,

p ros t a t i c c ance r i s i nh ib i t ed by dec rea s ing and rogen i c

h o r m o n a l f u n c t i o n a n d a c t i v a t e d b y i n c r e a s i n g t h e

a n d r o g e n s . M o r e o v e r , o u r d a t a , a s ye t u n p u b l i s h e d ,

show tha t i nh ib i t i on i s no t l im i t ed t o t he enzym e con-

t e n t o f s e r u m .

C e r t a i n b o n e d i se a se s , a s s h o w n b y K a y 9 ) , a r e

a s soc i a t ed w i th i nc r ea sed a lka l i ne phospha t a se ac t i v i t y

o f s e r u m a n d R o b e r t s i 4 ) d i s c o v er e d t h a t c e r t a in li v e r

d i s ea ses cause a s im i l a r i nc r ea se . A t t he p r e sen t t im e

e l e v a t i o n o f a l k a l i n e p h o s p h a t a s e o f s e r u m i s r e g a r d e d

as i nd i ca t i ng on ly bone o r hepa t i c d i s ea se . Th e re i s

n o e v i d e n c e t o s h o w t h a t h e p a t i c d a m a g e o c c u r s w i t h

f r e q u e n c y i n c a r c i n o m a o f t h e p r o s t a t e w h i l e e x t e n si v e

bone i nvo lv em en t by m e ta s t a s i s is o f t en obse rved . I t

c an be a s sum ed w i th l i t t l e r i sk t ha t e l eva t i on o f a l ka -

l in e p h o s p h a t a s e o f s e r u m i n c a r c i n o m a o f th e p r o s t a t e

i s u sua l l y due t o bone l e s ions , i n t he absence o f g ros s

e v i d e n ce o f h e p a t o p a t h y .

M a r k e d i n c r e a s e s i n a c i d p h o s p h a t a s e i n s e r u m h a v e

been obse rved on ly in p ros t a t i c c a r c inom a . R ob inson ,

G u t m a n , a n d G u t m a n I 5 ) f o u n d s l ig h t b u t d e fi n it e

e l eva t i ons o f t h i s enzym e the h ighe s t 8 . 7 un i t s ) i n

os t e i t i s de fo rm ans and s eve ra l o the r d i s ea se s w he re t he

b o n e s w e r e in v o l v e d . T h e d a t a i n t h e p r e s e n t p a p e r

ind i ca t e t ha t c a r c inom a o f t he p ros t a t e w i th ske l e t a l

m e ta s t a s i s i s som e t im es p r e sen t w i th s e rum ac id phos -

p h a t a s e v al u e s w i t h i n t h e n o r m a l r a n g e . H o w e v e r ,

w e f o u n d t h a t w h e n t h e r e w a s a m a r k e d r is e o f a ci d

p h o s p h a t a s e a b o v e i o u n i t s ) d i s s e m i n a t e d p ro s t a ti c

c a r c i n o m a w a s a l w a y s p r e s e n t .

G u t m a n a n d G u t m a n 6 ) o b s e rv e d t h a t t h e re w a s

n o c o r r e l a t io n b e t w e e n t h e h e i g h t o f s e r u m a c i d a n d

a l k a l i n e p h o s p h a t a s e s i n c a r c i n o m a o f t h e p r o s t a t e, a n d

i n g e n e r a l o u r d a t a a g r e e w i t h t h e i r f i n d in g s . T h i s

l ack o f co r r e l a t i on can now be exp l a ined . Th e e l e -

va t ed phospha t a se l eve l s i n ca r c inom a o f t he p ros t a t e

a r e due t o t he ac t i on o f tw o d i f f e r en t t ypes o f c e l l s ,

p ros t a t i c ep i t he l i um and os t eobl a s t s. Th e ac t i v i t y o f

p r o s ta t i c e p i t h e l i u m a s d e d u c e d f r o m t h e h e i g h t o f

s e r u m a c i d p h o s p h a t a s e ) i n d i s s e m i n a t e d c a n c e r o f

t he p ros t a t e depends a t l e a s t i n pa r t on t he deg ree o f

ac t i v i t y o f and rogens p r e sen t i n t he body , w he reas

e l eva t i on o f a l ka l i ne pho spha t a se i s depe nden t on i n -

c r ea sed os t eob l a s t i c f unc t i on a s a r e su l t o f i nvas ion o f

t he bones by t um or . I t is t hus app a ren t t ha t i nc r ea sed

a c i d a n d a l k a l i n e p h o s p h a t a s e a c t i v i t i e s i n s e r u m m a y

be cons ide red s epa ra t e ly s i nce t hey i nd i ca t e ac t i v i t y o f

d i f f e r en t t ypes o f c e l l s . The func t i on o f t hose ce l l s

c o n t r i b u t i n g t o t h e g r e a t e r p a r t o f t h e m o i e t y w h o s e

m a x i m u m o c cu r s a t p H 5 is d e p en d e n t o n a n d r o g e n

l eve l s , and can be i nc r ea sed o r dec rea sed by ad jus t i ng

the m a le s ex ho rm one l eve l .

H a v i n g e s t a b l is h e d a r e l a t io n s h i p o f a n d r o g e n i c h o r -

m ones t o ca r c inom a o f t he p ros t a t e , t he f i nd ings i n

the case o f O . A . F ig . 5 ) c an be i n t e rp r e t ed . I n t h i s

m a n t h e s e r u m a c i d p h o s p h a t a s e h a d b e e n g r e a t l y

inc rea sed by and rogen i n j ec t i ons and , f o l l ow ing ce s sa -

t i o n o f a n d r o g e n , t h e e n z y m e d e c r e a se d f o r i w e e k

w h e n i t w a s s u c c e e d e d b y a n a b r u p t s p o n t a n e o u s

seconda ry r i s e . The dec rea se fo l l ow ing ce s sa t i on o f

a n d r o g e n i n j e c t i o n m a y b e a s s u m e d t o b e t h e r e s u l t

o f t he dep re s s ion o f gonada l a c t i v i t y caused by and ro -

gen i n j ec t i ons a s i nd i ca t ed by M oore an d P r i ce x~ t ).

The subse quen t r i s e i s exp l a ined by pos tu l a t i ng t ha t

t he cance r ce l l s had been func t i ona l l y expanded by

a n d r o g e n a n d t h e r e f o r e r e s p o n d e d i n a n a u g m e n t e d

w ay t o ho rm ones p roduced by t he r ecove r ing t e s t i s .

C a s t r a t i o n c a u s e d a m a r k e d d e c r ea s e o f s e r u m a c i d

phospha t a se bu t i n som e ca se s t he enzym e l eve l d id

no t r each no rm a l w h i l e i n o the r s i t l ay i n a r ange a t

t h e u p p e r l i m i t o f n o r m a l v a l u e s. M u c h p r o o f h a s b e en

a d d u c e d t h a t a n d r o g e n i s p r o d u c e d i n e x t r a g o n a d a l

l oc i e spec i a ll y i n t he sup ra r ena l g l an d . Th e m os t r eady

e x p l a n a t i o n f o r v a r i a t i o n s i n s e r u m a c i d p h o s p h a t a s e

l eve l s f o l l ow ing 0 rch i ec tom y a s w e l l a s t he f a i l u r e o f

s o m e v a l u e s t o r e a c h t h e n o r m a l r a n g e m a y b e p o s t u -

l a t e d b y a s s u m i n g v a r y i n g a m o u n t s o r a c t i v i t y o f

a n d r o g e n s p r o d u c e d i n e x t r a g o n a d a l s o u r c e s i n d i f -

f e r e n t i n d i v id u a l s . I t m u s t b e p o i n t e d o u t h o w e v e r

t h a t u r i n a r y a s s a y s o f h o r m o n e e x c r e t io n w e r e n o t d o n e

i n t h i s s t u d y . F r o m t h e e v i d e n c e o n e c a n n o t e x c l u d e

the pos s ib i l i ty t h a t l oc i o f m e t a s t a t i c c a r c inom a a s w e l l

a s t he o r i g ina l s i t e m igh t a f f ec t t he l eve l s o f phospha -

t a s e a n d s o m a i n t a i n t h i s e n z y m e a t a n a b n o r m a l l y

h i g h r a n g e e v e n t h o u g h t h e r e w e r e n o a n d r o g e n s

p r o d u c e d i n e x t r a g o n a d a l a r e a s . A g a i n s t t h i s a l t e r n a -

t i ve exp l ana t i on i s t he f ac t t ha t a t roph i c p ros t a t i c t i s sue

c o n t a in s m e r e l y t r a c es o f a c i d p h o s p h a t a s e a s G u t m a n

a n d G u t m a n 5 ) f o u n d i n t h e i n f an t il e h u m a n p r o s ta t e

g l a n d .

N one o f t he phospha t a se s ha s been i so l a t ed a s ye t






H ug gin s et al. Ser um Phosphatase and Prostatic Cancer

2 9 7

in a pu re s t a t e . Th e f i nd in gs o f none o r sm a l l am ou n t s

o f t he se enzym es i n ce r eb rosp ina l o r spe rm a toce l e

f l u ids show tha t t he enzym es a r e m o lecu l e s w h ich do

n o t c r o s s c e r t a i n m e m b r a n e s r e a d i l y f r o m t h e b l o o d

and a r e no t i ncons i s t en t w i th t he ev idence o f K u t sche r

a n d P a n y 1 2 ) t h a t p h o s p h a t a s e is a p r o t e in .

S U M M A R Y A N D C O N C L U S I O N S

~ . The con t en t i n s e rum o f phospha t a se w i th ac t i v i t y

m a x i m u m a t p H 5 i n n o r m a l m e n a n d i n m e n w i t h

benig n pros ta t ic hy per t rop hy was 3 .25 ___ ~ .37 Ki ng and

A r m s t r o n g u n i t s i n ~ oo c c. S e r u m p h o s p h a t a s e w i t h

a c t iv i ty m a x i m u m a t p H 9 .3 i n t h is c o n t ro l g r o u p w a s

7 . 9+ 2 . i un i t s i n IOO cc .

2 . I n a g r ou p o f 2 5 m en w i th roen tgeno log i c ev i -

dence o f m e t a s t a t i c c a r c ino m a to t he bony pe lv i s, bo th

ac id and a lka l i ne phospha t a se s w e re i nc r ea sed above

norm a l i n 19 ca se s , on ly a lka l i ne phospha t a se w as i n -

c r ea sed i n 2 ca se s , and bo th va lues w e re w i th in no rm a l

l im i t s i n 4 ca se s . M e ta s t a t i c c a r c inom a o f t he p ros t a t e

m a y b e p r e s e n t i n b o n e s w h e n t h e p h o s p h a t a s e s o f

s e r u m a r e n o r m a l , b u t w h e n a c i d p h o s p h a t a s e i s

p r e sen t i n ac t i v i t y g r ea t e r t han xo unit s i n i oo cc. , dis-

s em ina t ed p ros t a t i c c ance r i s p r e sen t .

3 . I n p ros t a t i c c ance r w i th m arked e l eva t i on o f ac id

phospha t a se , c a s t r a t i on o r i n j ec t i on o f l a rge am oun t s

o f e s t r o g e n c a u s e d a s h a r p r e d u c t i o n o f t h i s e n z y m e

t o o r to w a r d s t h e n o r m a l r a n g e . A l k a l i n e p h o s p h a t a s e

va lues ro se fo l l ow ing ca s t r a t i on and t hen dec rea sed , bu t

m o re s low ly t han ac id phospha t a se . I n ce r t a i n ca se s ,

t h e s e v a l u e s r e a c h e d a n d w e r e m a i n t a i n e d i n a n o r m a l

r ange du r ing t he pe r i od o f obse rva t i on , 18o days ,

w h i l e i n o the r pa t i en t s t he va lues w e re s l i gh t l y above

n o r m a l .

4 . I n 3 pa t i en t s w i th p ros t a t i c c ance r , an d rog en

in j ec t i on caused a sha rp r i s e o f s e rum ac id phospha t a se .

In i c a se fo l l ow ing ce s sa t i on o f and roge n t he r e w as a

dec rea se o f t he ac id phospha t a se fo l l ow ed by a s econ-

da ry spon t aneous r i s e .

5 . A c id ph osph a t a se does no t r ead i l y c ross m e m -

branes f rom the b lood , s i nce i t w as p r e sen t on ly i n

t r ace s i n ce r eb rosp ina l and spe rm a toce l e f l u id s w hen

c o n c u r r e n t s e r u m l e v e l w a s h i g h .

6 . P ros t a t i c c ance r i s i n f l uenced by and rogen i c ac -

t i v i t y i n t he body . A t l e a s t w i th r e spec t t o s e rum

phospha t a se s , d i s s em in a t ed ca r c in om a o f t he p ros t a t e

i s i n h i b i t e d b y e l i m i n a t i n g a n d r o g e n s , t h r o u g h c a s t r a -

t i on o r neu t r a l i z a t i on o f t he i r a c t i v i t y by e s t rogen

in j ec t i on . C an ce r o f t he p ros t a t e i s a c t i va t ed by

a n d r o g e n i n j e c t i o n s .

R E F E R E N C E S

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d u r c h d a s p H W i r k u n g s o p t i m u m u n t e r s c h e id b a r e n P h o s -

p h o es t e r a s en i n t i e r i sch en Org an en . Z t s ch r . f . p h y s i o l .

C h e m . , 2 : 2 9 : 1 2 5 - 1 5 o . 1 9 3 4 .

2. BARRINGER,B. S . , and H. Q. WOODARD. Pros tat i c C arc inom a

wi t h E x t en s i v e In t r ap ro s t a t i c C a l c if i ca ti o n . T r . Am . A .

G e n i t o - U r i n . S u r g e o n s , 3 I : 3 6 3 - 3 6 9 . 1 9 3 8 .

3 . DAVIES , D . R . P h o s p h a t a s e Ac t i v i t y o f S p l een E x t r ac ts . B i o -

ch em . J . , 2 8 : 5 2 9 -5 3 6 . 1 9 3 4 .

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Gl y ce ro p h o s p h a t a s e in t i e r is ch en Org an en . B i o ch em .

Z t s ch r ., 3 9 : 1 -5 . 1 9 1 2 .

5 . GUT M AN, A . B . , an d E . B . GUT M AN. " Ac i d " P h o s p h a t a s e

an d F u n c t i o n a l Ac t i v i t y o f th e P ro s t a te (M an ) an d

P rep u t i a l G l an d s (R a t ) . P ro c . S o c . E x p e r . B i o l. & M ed . ,

3 9 : 5 2 9 - 5 3 2 9 I 9 3 8 .

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Occu r r i n g i n t h e S e ru m o f P a t i en t s w i t h M e t as t a s i z i n g

C arc i n o m a o f t h e P ro s t a t e G l an d . J . C l i n . I n v es t i g a t io n ,

I 7 : 4 7 3 - 4 7 8 - 1 9 3 8 .

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can ce o f In c reas ed P h o s p h a t a s e A c t i v i t y a t t h e C i t e o f

Os t eo p l a s t i c M e t as t a s e s S eco n d a ry t o C a rc i n o m a o f t h e

P ro s t a t e G l an d . Am . J . C an ce r , 2 8 : 4 8 5 - 4 9 5 . 1 9 3 6 .

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2 5 3 -2 5 6 . 1 9 2 9 .

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M . A . J . , 3 1 : 3 7 6 - 3 8 1 . 1 9 3 4 . :J

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1941;1:293-297.Cancer Res

Charles Huggins and Clarence V. Hodges

in Metastatic Carcinoma of the ProstateEstrogen and of Androgen Injection on Serum PhosphatasesStudies on Prostatic Cancer. I. The Effect of Castration, of

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