[CANCER RESEARCH 33, 849-855, April 1973]
Suppression of Pituitary Tumor Growth and Function by Ergot
Alkaloids1' 2
Robert M. MacLeod3 and Joyce E. Lehmeyer
Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22901
SUMMARY
The in vivo and in vitro effects of ergot derivatives on
prolactin and growth hormone biosynthesis in the rat have
been studied. Injection with 0.05 or 0.2 mg ergotamine
tartrate had no effect on in vitro prolactin synthesis by the
pituitary gland. Ergocornine and ergocryptine, however,
inhibited both synthesis and release of prolactin. Incubation of
glands with 4 or 40 /nM ergotamine greatly decreased prolactin
synthesis and release but had no effect on growth hormone.
Ergocornine,
10 /¿M,and ergocryptine,
10 juM, almost
completely blocked prolactin release and decreased synthesis
and release of growth hormone as well.
Daily administration of 0.05 mg ergotamine for 13 days to
rats bearing the prolactin- and adrenocorticotropic hormonesecreting pituitary Tumor 7315a dramatically inhibited tumor
growth and reversed the adrenal hypertrophy caused by the
tumor adrenocorticotropic
hormone.
Ergotamine,
ergo
cryptine, and ergocornine were all effective in suppressing the
growth of pituitary
tumors and reversed the splenohepatomegalia caused by growth hormone-secreting tumors. In
addition, the ergots decreased the high circulating prolactin
levels found in tumor-bearing animals. Ergotamine alone was
able to overcome the atrophy of the pituitary glands of
tumor-bearing animals and allow gland function to return
toward normal. Ergocryptine and ergocornine tended further
to suppress gland function. These data demonstrate that
hormone synthesis and release by the pituitary gland and
pituitary tumors can be inhibited by derivatives of the ergot
alkaloids.
INTRODUCTION
For the past several years, investigations in this laboratory
have been directed toward the mechanisms governing the
function of the pituitary gland and the function of pituitary
tumors. More specifically, we have been interested in the
endocrine mechanisms involved in prolactin synthesis and
release by the pituitary gland and have been ultimately
concerned with the role of this hormone in supporting
1This investigation was supported by USPHS Grant CA-07535 from
the National Cancer Institute.
'Portions of this work were presented at the Annual Meeting of the
American Association for Cancer Research, 1972.
'Investigation conducted while a recipient of Research Career
Development Award CA-07665 from the National Cancer Institute.
Received September 5, 1972; accepted January 8, 1973.
mammary tumorigenesis. Among the drugs that are of
considerable interest in control of prolactin release are the
ergot alkaloids.
Nagasawa and Meites (9) and Wuttke et al. ( 14) have shown
that ergocornine in vivo decreases serum and pituitary
prolactin levels. When added in vitro, it decreases the release of
prolactin by the pituitary gland (3). It has also been shown
that both ergocornine and ergocryptine inhibit the growth of
7,12-dimethylbenzanthracene-induced
mammary tumors (1,9)
and the growth of spontaneous mammary tumors as well (12).
Yanai and Nagasawa (16) demonstrated that ergocornine
inhibited the appearance of spontaneous mammary tumors
and suppressed prolactin secretion in mice. Recently, we
reported our finding that ergotamine, ergocryptine, and
ergocornine were all effective in suppressing growth of several
pituitary tumors (7). Similarly, Quadri et al. (11) found that
injection of ergocornine or ergonovine induced regression of
the growth of the prolactin-secreting
pituitary Tumor
MtTWIS.
The present study is in agreement with these latter reports
on the effects of ergot alkaloids on pituitary tumors.
Additionally, the work presented here demonstrates that the
primary effect of ergotamine on animals bearing pituitary
tumors is a direct, suppressive effect on the tumor itself, rather
than on the pituitary gland of the host.
MATERIALS AND METHODS
Animals. Mature Wistar-Furth rats (obtained from A. R.
Schmidt Co., Inc., Madison, Wis.) were inoculated with
pituitary Tumors MtTWS, MtTWIS, and SMtTWS as pre
viously described (5). Pituitary Tumor 7315a was transplanted
into mature female Buffalo rats (obtained from Simonsen
Laboratories, Gilroy, Calif.). Mature female Sprague-Dawley
rats were obtained from Flow Research Animals, Dublin, Va.
All rats were routinely housed 4 to 5/cage at 22—23°and
allowed water and Purina laboratory chow ad libitum.
Materials. Tissue Culture Medium 199 was obtained from
Microbiological Associates, Bethesda, Md. Leucine-4,5-3H,
29.8 Ci/mmole, was a product of International Chemical and
Nuclear Corp., Irvine, Calif. Ergotamine tartrate, ergocryptine,
and ergocornine maléatewere gifts from Sandoz Pharmaceuti
cals, Hanover, N. J. In some cases, the ergotamine tartrate
injected was Gynergen (Sandoz). The drugs were all injected
s.c.
Organ Culture. Incorporation of leucine-4,5-3H into prolac
tin and growth hormone was studied by incubating bisected
pituitary glands in 0.5 or 1 ml of Tissue Culture Medium 199
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849
Robert M. MacLeod and Joyce E. Lehmeyer
containing 5 to 10 juCi of leucine-4,5-3H. Flasks were
incubated for 6 to 7 hr at 37°in a Dubnoff shaker and were
gassed with 95% O2 -5% C02 . Pituitary glands were homoge
nized in 0.5 to 1 ml of 50 mM phosphate (pH 7.2) with a glass
homogenizer fitted with a Teflon pestle. Homogenates were
frozen and thawed 3 times to lyse all granules. Duplicate
aliquots (50 //I) were then subjected to polyacrylamide gel
electrophoresis (4), with the sample, stacking, and separating
gel system of Jones et al. (2). The incubation medium proteins
were separated on gels as well, but the 50-/J.I aliquots were
"top-loaded" according to the system described by Reisfeld et
al. (13). The proteins on the gels were stained with Amido
black and band quantitated by means of a Canalco microdensitometer with an integrator. The hormone bands on the
gels were identified by comparing their mobility with purified
preparations of prolactin and growth hormone. Our results are
in excellent agreement with those of Jones et al. (2), who
eluted these proteins from the polyacrylamide gels and
established their identity by bioassay. After the identity of the
hormone bands was established, the bands were cut, placed in
counting vials, and dissolved in 0.5 ml 30% HjC^ at 100°.
After addition of a Triton-toluene counting solution, the vials
were placed in a scintillation counter to determine the level of
radioactivity.
Prolactin Radioimmunoassay. The immunoassay of sera and
incubation media was carried out using the reagents and
PROLACTIN
10
rii
*
o
I
t^•I—i-i-Controi1Hh»HW1T 1M n u Km U N
a
*•Tj'-I-_!>_-I-Ergotamin«
Ergocty0.05
mg doily
Control
Ergotomin«
0.2 mg daily
Control
Ergocor
tini0.2
nini
mgdoily
mg 0.2
daily
Chart 1. Effect of administration of ergot derivatives on in vitro
synthesis and release of prolactin and growth hormone. Bisected female
rat pituitary glands were incubated with leucine-4,5-3H for 6 to 7 hr.
The prolactin and growth hormone in the incubation medium and in
the tissue were separated by polyacrylamide gel electrophoresis, and the
radioactivity in the hormone bands was measured by scintillation
counting techniques. Animals were treated by daily injection s.c. for 7
days. / bars, mean ±S.E. of duplicate determinations on 2 to 3
incubation flasks, each containing 4 randomized pituitary gland halves.
850
protocol supplied by the Hormone Distribution Program,
National Institute of Arthritis and Metabolic Diseases. The
prolactin provided was iodinated either with '2 51 or '3 ' I,
obtained from New England Nuclear, Boston, Mass. Sheep
anti-rabbit y-globulin was obtained from Dr. Ann J. Johanson
of the University of Virginia Medical School.
Statistical Analysis of Experimental Data. When appro
priate, results are expressed as the mean ± S.E. The
significance of the difference between the means was
determined by Student's t test.
RESULTS
The effects of ergot alkaloids on pituitary gland function in
normal female rats are illustrated in Chart 1. The open bars in
the chart represent the labeled prolactin or growth hormone
found in the incubation medium at the termination of the
incubation. The open bars, therefore, indicate "release" of
newly synthesized hormone into the medium during the
incubation period. The shaded bars represent the labeled
prolactin or growth hormone found in the pituitary tissue at
termination of incubation. The total height of both the open
and shaded bars is the sum of the newly synthesized hormone
released into the medium and that remaining within the tissue
and is termed "total synthesis." Daily injection of 0.05 or 0.2
mg ergotamine tartrate for 7 days had no effect on the release
of prolactin by the pituitary gland or on total in vitro
synthesis of prolactin. The injection of ergocornine, however,
resulted in a decrease in release of newly synthesized prolactin
into the incubation medium (open bar) and a subsequent
accumulation of the labeled hormone within the pituitary
gland (shaded bar). There was no significant effect on total
prolactin synthesis. Ergocryptine injection almost completely
blocked prolactin release. Newly synthesized prolactin accu
mulated within the tissue (shaded bar), but total synthesis was
decreased compared with the control. Injection of 0.2 mg of
the drugs resulted in a slight increase in total growth hormone
synthesis. This increase in growth hormone synthesis may be
an example of the reciprocal relationship between prolactin
and growth hormone, a preliminary report on which has
recently appeared (8).
The in vitro effects of the ergots are shown in Chart 2.
Although ergotamine had no effect on in vitro pituitary
hormone synthesis when injected (Chart 1), incubation of
pituitary glands with a 4 ¿/Mdrug concentration resulted in a
greatly decreased release of prolactin into the medium (open
bar) and a subsequent accumulation of labeled prolactin
within the tissue (shaded bar). Total in vitro synthesis of
prolactin was also significantly decreased with respect to the
control. At 40 /^M, the effect of ergotamine on release and
total synthesis of prolactin was even more pronounced. No
effect on growth hormone production was observed. Ergocor
nine and ergocryptine, 10 juM, almost completely blocked
release of prolactin (open bar) and greatly decreased total
synthesis as well. Growth hormone synthesis and release were
inhibited to a lesser extent.
Daily administration of 0.05 mg of ergotamine for 13 days
to animals bearing the prolactin- and ACTH4-secreting
4The abbreviation used is: ACTH, adrenocorticotropic
hormone.
CANCER RESEARCH VOL. 33
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Ergots and Pituitary Tumors
PROLACTIN
Medium
Gland
6
rii
5
4
3
î" 2
a
'5
E
'
o>
n
O
GROWTH
HORMONE
rii
E
a
Control
Control 4xlO-*M
Ergotamine
Tarliate
IO-5M 10-5M
Etgocor Ergocrypnine
tine
summarized in Table 1. Injection treatment of normal rats
with 0.2 mg ergocryptine or ergocornine for 7 days had no
effect on body weight or on the weights of the pituitary gland,
the spleen, or the adrenals. Ergocornine slightly but signifi
cantly decreased liver weight (Group 1 versus Group 3).
Injection treatment of normal rats for 7 days with 0.2 mg
ergotamine decreased body weight 12% but had no effect on
the weight of the pituitary gland, liver, or spleen. Interestingly,
the weight of the adrenals was actually increased.
Growth hormone-secreting pituitary tumors are known to
cause marked splenohepatomegalia (6, 17). Implantation of
the SMtTWS tumor resulted in increased body weight and
increased liver and spleen weight; the weight of the pituitary
gland was greatly decreased (Group 4 versus Group 6). When
animals bearing these tumors were given injections of
ergotamine (Group 6 versus Group 7), the size of the tumor,
the liver, and the spleen were all decreased, and the previously
suppressed pituitary gland returned to almost normal control
weight. Ergocornine treatment also reduced tumor, liver, and
spleen size but did not relieve the suppression of the pituitary
gland of the host (Group 8 versus Group 9). Similarly,
ergocryptine decreased tumor weight but did not affect
pituitary gland weight (Group 10 versus Group 11).
Treatment of rats bearing the prolactin- and ACTH-secreting
pituitary Tumor 731 Sa with 0.05 mg ergotamine for 13 days
had no effect on body weight, but tumor size was greatly
decreased and the adrenal hypertrophy caused by the tumor
ACTH was reversed (Group 12 versus Group 13).
The 731 Sa and MtTWS tumors secrete large amounts of
prolactin. Consequently, circulating prolactin levels in rats
bearing these tumors are 10 to 200 times greater than in non
tumorous animals (Chart 4). Injection treatment of normal
female Buffalo rats with ergotamine had no significant effect
Chart 2. In vitro effect of ergot alkaloids. Bisected pituitary glands
were incubated with the ergot derivatives at the concentrations
indicated in the chart. / bars, mean ±S.E. of duplicate determinations
on 2 to 3 incubation flasks, each containing 4 randomized pituitary
gland halves.
pituitary Tumor 7315a dramatically inhibited tumor growth
(Chart 3A), despite the fact that injection of ergotamine
produced only minimal endocrine changes in the pituitary
glands of nontumorous female rats. While the tumors of the
nontreated animals increased 89% in size, the tumors of the
injection-treated animals increased only 22%.
Rats bearing the SMtTWS and MtTWIS tumors, which
secrete both prolactin and growth hormone, were given daily
injections of 0.2 mg ergotamine tartrate for 7 days. Again,
tumor growth was greatly inhibited (Chart 3, B and C,
respectively).
The efficacy of ergocryptine and ergocornine in retarding
tumor growth is illustrated in Chart 3, D and E. Six daily
injections of 0.2 mg ergocryptine suppressed growth of the
MtTWS tumor, which secretes both prolactin and growth
hormone (Chart 3D). Treatment with ergocornine maléatealso
inhibited growth of the SMtTWS tumor (Chart 3F).
The effects of administration of ergot derivatives on organ
weights of normal and pituitary tumor-bearing rats are
DAYS OF INJECTION
Chart 3. Effect of ergot treatment on pituitary tumor growth. Rats
bearing transplanted, hormone-secreting pituitary tumors were given
daily s.c. injections of 0.05 mg ergotamine tartrate (A), 0.2 mg
ergotamine tartrate (B, C), 0.2 mg ergocryptine (D), and 0.2 mg
ergocornine maléate(£").
The tumors studied were 7315a (A), SMtTWS
(B, E), MtTWIS (O, and MtTWS (D). The number of animals used in
each experiment were 6 untreated, 6 treated (A); 4 untreated, 4 treated
(B); 3 untreated, 3 treated (C); 5 untreated, 5 treated (D and E).
Vertical lines, S.E.
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851
Robert M. MacLeod and Joyce E. Lehmeyer
Table 1
Effect of ergot treatment on tissue weights of tumor-bearing rats
Wt/100gbodywt
of
wt
tumor
gland
Group12345678910111213GroupControlErgocryptine"Ergocornine0ControlErgotamine0SMtTWSSMtTWS
animals6444444555566Body
(mg)4.91
(g)23.8
(g)195
(g)4.50
±186188197175254193
±10.4±7.1
(g)0.28
0.324.58
±
0.074.39
±
0.164.48
±
0.014.54
±
0.362.62
±
0.03d4.25
±
0.04d3.05
±
0.094.35
±
0.314.05
±
8b2.80±0.1
0.103.00
±
0.045.00
±
0.37d3.54
±
2d5.32±0.1
0.134.51
+
0.04d4.21
±
+ergotamine0SMtTWSSMtTWS
±225
+ergocornine"MtTWSMtTWS
±186
±226
±2.3
±21.4
0.253.92
±
0.073.29
±
+ergocryptine07315a731Sa
±201
±236
±8.8
±12.7
0.313.43
±
0.273.28
+
0.020.260.260.310.280.560.320.590.310.010.
237±
438±
226±
±236±2C21
lb30±
ld26±
131±
±276+
0.153.45
±
±229
±1.9
0.123.73
±
±0.02dSpleen
+6.72.61.20.2d6.72.13.40.3dPituitary
±34253d82d55d135125Pituitary
±0.27Liver
+ergotamine8No.
(mg)41
1030±2d
0 Animals received 0.2 mg ergot daily for 6 to 7 days.
b p < 0.05; Groups 1 vs. 3,4 vs. 6.
cp< 0.025 ¡Groups4 vs. 5,4 vs. 6, 8 vs. 9.
d p < 0.01; Groups 4 vs. 5,4 vs. 6, 6 vs. 7,8 vs. 9, 12 vs. 13.
e Animals received 0.05 mg ergot daily for 13 days.
on circulating prolactin levels. The control Buffalo rats had
prolactin levels of 120.4 ±17-5 ng/ml while the injectiontreated rats had levels of 149.5 ±31.8 ng/ml. We have
consistently found the circulating levels of prolactin in the
Buffalo strain to be much higher than in other strains of rats.
Immunoassay of serum from Sprague-Dawley female rats gave
prolactin values of 29.6 ±2.2 ng/ml. The meaning of this is
not now clear. The animals bearing the 7315a tumors had
20000 r-
15000
-t
n
5000
-5
1000
55
I
-I
800
600
400
200
n
Non-tumor
n
Non-tumor
+
Ergotamine
7315o
7315o
+
Ergotamine
MtTWS
MtTWS
+
Ergocryptine
Chart 4. Effect of ergot treatment on serum prolactin. Serum
prolactin levels in normal female rats and in rats bearing pituitary
tumors were measured by radioimmunoassay. Serum samples from 3 to
6 animals/group were assayed in duplicate.
852
circulating prolactin levels in excess of 3000 ng/ml. Treatment
with ergotamine reduced the level to 1200 ng/ml. Similarly,
injection treatment of animals bearing the MtTWS tumor with
ergocryptine reduced serum prolactin levels from in excess of
3000 ng/ml to 960 ng/ml. The normal Wistar-Furth female rats
used for controls had serum prolactin levels of 15.4 ±0.8
ng/ml.
We have previously reported that pituitary gland function is
greatly reduced in rats bearing hormone-producing pituitary
tumors (4). The in vitro synthesis of prolactin by glands of
normal animals and animals bearing the 7315a tumor is
illustrated in Chart 5. Again, ergotamine treatment had no ef
fect on the in vitro release of prolactin (open bars) or on total
synthesis by glands of normal animals. The glands of rats
bearing the 7315a tumor synthesize and release much less
prolactin than do glands of normal animals. This situation
presumably occurs via an autofeedback mechanism due to the
greatly elevated circulating levels of prolactin (Chart 4).
Ergotamine treatment of animals bearing this tumor sup
pressed tumor growth (Chart 3/1), thus decreasing the serum
prolactin level (Chart 4). Consequently, the in vitro release and
synthesis of prolactin by the glands of these animals
rebounded toward normal (Chart 5). The radioimmunoassay
on the incubation media also shows that ergotamine treatment
had no effect on the in vitro release of prolactin by normal
glands. The glands of the tumor animals release much less
prolactin than do normal glands, but suppression of tumor
growth by injection of ergotamine allowed in vitro prolactin
release to increase.
Similar experiments with animals bearing other pituitary
tumors are summarized in Table 2. As was seen earlier,
ergotamine treatment had no effect on total in vitro prolactin
synthesis or release by the glands of control animals
CANCER
RESEARCH
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33
Ergots and Pituitary Tumors
5
I
e
0_
o>
E
CONTROL
CONTROL 7315o
ERGOTAMINE
7315o
ERGOTAMINE
CONTROL
CONTROL 7315a
ERGOTAMINE
7315o
ERGOTAMINE
Chart 5. Effect of administration of ergotamine on in vitro prolactin synthesis. Six normal female
rats and 6 female rats bearing the prolactin- and ACTH-secreting pituitary Tumor 7315a were given
daily injections of 0.05 mg ergotamine tartrate for 7 (normal rats) or 13 (tumor rats) days. The
pituitary glands were incubated as described in Chart 1. Left, in vitro synthesis and release of
prolactin. T-bars, mean ±S.E. of duplicate determinations on 3 incubation flasks, each containing 4
randomized pituitary gland halves. Right, results of a prolactin radioimmunoassay on the incubation
media. T-bars, mean ±S.E. of triplicate determinations on each of the 3 incubation flasks in each
group.
(Experiment 1). The glands of rats bearing the SMtTWS tumor
synthesized and released significantly less prolactin than did
control glands. Treatment of animals bearing this tumor with
ergotamine tartrate suppressed tumor growth (Chart 35) and
allowed the in vitro synthesis and release of prolactin by the
glands of the treated animals to increase significantly. Total
synthesis of labeled prolactin increased 104% and release
increased 87% (Group 3 versus Group 4). The radioimmuno
assay of the incubation media suggested a small although
nonsignificant increase in release of total prolactin (i.e.,
pre-formed as well as newly synthesized).
In Chart 1 it was shown that injection of ergocornine,
unlike ergotamine, had a direct, suppressive effect on prolactin
synthesis by the gland. When animals bearing the SMtTWS
tumor were treated with ergocornine, tumor growth was
retarded (Chart 3E). The synthesis and release of labeled
prolactin by the pituitary glands of the hosts were decreased,
although the effect was not statistically significant. (Table 2,
Experiment 2). The radioimmunoassay also strongly suggested
a decrease in release of prolactin into the incubation medium
although, again, the difference was not statistically significant.
Experiment 3 illustrates the direct, suppressive effect of
ergocryptine injection on in vitro prolactin synthesis and
release. The 98% decrease in release of labeled prolactin was
accompanied by an accumulation of the hormone within the
gland. Total synthesis was decreased 85%. The decrease in
release as measured by radioimmunoassay was highly signifi
cant.
Implantation of the MtTW5 tumor resulted in decreased in
vitro synthesis and release of prolactin by the pituitary glands
of the host animals (Experiment 4). When animals bearing this
tumor were treated with ergocryptine tumor growth was
inhibited (Chart 3D), synthesis and release of labeled prolactin
by the glands of the host were even further suppressed.
The effect of ergotamine in the in vitro synthesis of growth
hormone is shown in Experiment 5. Injection treatment of
male rats with the drug had no significant effect on synthesis
or release of labeled growth hormone. Implantation in male
rats of the growth hormone-secreting pituitary Tumor MtTWl 5
decreased in vitro growth hormone synthesis by the glands of
the hosts by 55% (Group 122 versus Group 14). Release of
labeled hormone into the medium was reduced 51%. Treat
ment of animals bearing this tumor suppressed growth of the
tumor (Chart 3C) and tended to relieve the suppression of the
host glands. Release of growth hormone was significantly
greater when compared to release by glands of untreated
tumor-bearing animals (Group 14 versus Group 15).
DISCUSSION
The present report verifies the previous finding (3, 7,9,14,
15) that the administration of ergocornine and ergocryptine to
normal female rats suppresses release and, to a lesser extent,
synthesis of prolactin. Ergocryptine and ergocornine in vitro,
however, not only blocked prolactin release and, subsequently,
synthesis, but they inhibited release and synthesis of growth
hormone as well. The injection of ergotamine was without
effect on in vitro prolactin production. Nicoli et al. (10) were
able to demonstrate that ergotamine tartrate injected at 5
times the amount used in the current experiments caused a
40% decrease in prolactin secretion in vitro. Ergotamine in
vitro was partially effective in reducing prolactin production
but had no effect on growth hormone. Consequently, it is
unclear whether the administered ergots exert their effects by
acting directly on the gland or by indirect means. Wuttke et al.
(14) have recently proposed that ergocornine acts via the
hypothalamus to decrease pituitary function although a direct
action of the drug was not excluded.
It has been clearly demonstrated (1, 9, 12, 15, 16) that
ergot treatment can inhibit growth of mammary tumors. A
recent report showed that ergocornine and ergonovine could
suppress growth of a prolactin-secreting pituitary tumor (11).
We have found (7) that the administration of ergotamine
tartrate, as well as ergocryptine and ergocornine, causes
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853
Robert M. MacLeod and Joyce E. Lehmeyer
Table 2
Effect of ergot treatment on in vitro prolactin and growth hormone synthesis
Rats were treated by s.c. injection of 0.2 mg ergot daily for 6 to 7 days. Pituitary glands were incubated, and newly
synthesized, labeled hormone was measured as described in Chart 1. Prolactin concentration in the media was measured by
radioimmunoassay. The values presented are the means ±S.E. of duplicate determinations on 2 to 3 incubation flasks, each
containing 3 to 5 randomized pituitary gland halves, except in Experiment 4, in which single glands were incubated
individually.
pituitary)Medium
(cpm/mg
ofanimalsProlactin
Group
GroupNo.
Gland
TotalProlactin
(Mg/mgpituitary in
medium)
Experiment I
1
2
3
4
Control
Ergo lamine
SMtTWS
SMtTWS +
ergo ta mine
4
4
4
4
4838 ±241
5311 ±376
1720 ±23°
3223±210°
1230±124
1013± 70
131 ±47°
551± 104
6068
6324
1851
3774
+ 117
±306
± 24b
±106b
16.0
16.0
13.0
14.5
±0.5
±1.5
±1.0
±0.5
Experiment 2
SMtTWS
SMtTWS +
ergocornine
2566 ±393
1648 ±213
Control
ergocryptine
3437± 189
84 ±176
182± 18
326±182
2748 ±376
1974 ± 31
2.9 ±0.9
0.9 ±0.0
3481 ±196
507 ± 37&
5.2 ±1.7
0.7 ±O.lb
Experiment 3
44 ± 8
423± 48b
Experiment 4
9
10
MtTWS
+ergocryptine4
11Control MtTW5
553022
±385
± 72
1006 ±104b
268 ± 15b
301
67bMedium922
±IIIeTotalExperiment
91CGrowth
540 ±
±440
1274±109b
841 +
hormone(cpm/mg
pituitary)Gland3944
.512131415ControlErgotamine
MtTWISMITW15
+ergotamine33
331273
1001419
±
1002726
±
± 28
± 6
625
8C934+
±
1428
112°1769
±
47a3251
±1354524
2804145
+
± 37
2053
166°2703+
±
53
" p< 0.025; Groups 1 vs. 3, 3 vs. 4, 12 vs. 14, 14 vs. 15.
6 p < 0.005; Groups 1 vs. 3, 3 vs. 4, 7 vs. 8, 9 vs. 10, 10 vs. 11.
c p< 0.05; Groups 10 vs. 11, 12 vs. 14.
inhibition of growth or even actual regression of several
hormone-producing
pituitary tumors. Suppression of tumor
growth is accompanied by a decrease in serum prolactin levels
and a reversal of the tumor hormone-induced organ hypertro
phy. Of the 3 alkaloids, only ergotamine showed a specificity
for the tumor. The glands of the host animals were not further
suppressed by treatment with the alkaloid. After the expected
decrease in circulating prolactin following tumor suppression,
the glands of these animals synthesized increased amounts of
prolactin. When tumor-bearing animals were given ergo
cryptine or ergocornine, the glands of the host animals were
even further suppressed, in spite of a reduction in serum
prolactin levels.
It would be of interest to learn whether the pituitary tumor
854
contains an ergotamine-sensitive receptor site which is not
found in the gland. This specificity for the tumor suggests that
ergotamine might be of clinical importance in the treatment of
pituitary tumors.
The fact that ergot derivatives decrease serum prolactin and
leutinizing hormone (14) suggests that the drugs have a general
suppressive effect on pituitary function rather than a specific
effect on selected pituitary cell receptors. Additionally, the
drugs presumably decrease ACTH secretion by the pituitary
tumors since the ergots cause atrophy of the adrenal glands.
Because ergot alkaloids have a vasoconstrictive effect, there is
a strong possibility that the decreased pituitary gland and
tumor function may result from this action.
CANCER RESEARCH VOL. 33
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Ergots and Pituitary Tumors
ACKNOWLEDGMENTS
We would like to thank Mr. Ronald C. Pace for his excellent
technical assistance.
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APRIL 1973
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855
Suppression of Pituitary Tumor Growth and Function by Ergot
Alkaloids
Robert M. MacLeod and Joyce E. Lehmeyer
Cancer Res 1973;33:849-855.
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