Download Effects of Cancer Chemotherapeutic Agents on Endocrine Organs

[CANCER RESEARCH 35, 1975-1980, August 1975]
Effects of Cancer Chemotherapeutic Agents on Endocrine Organs
and Serum Levels of Estrogens, Progesterone, Prolactin, and
Luteinizing Hormone'
Eric V. H. Kuo, Henry J. Esber, D. Jane Taylor, and Arthur E. Bogden
Department oflmmunobiology, Mason ResearchInstitute, Worcester,Massachusetts01608 [E. Y. H. K., H. J. E., A. E. B.], and Division of Cancer
Biology and Diagnosis,National CancerInstitute, Bethesda,Maryland 21.Xfl4[D. J. T.]
SUMMARY
INTRODUCTION
The effects of the following cancer chemotherapeutic
agents on serum hormonal
levels, estrous cycles, and
endocrine
organs
were studied
in mature,
normal
Sprague-Dawley
rats by radioimmunoassay,
vaginal smear
examination, and organ weight end point: estradiol mustard
(NSC 112259), testosterone mustard (NSC I 12260), phen
estrin (NSC 104469), methotrexate
(NSC 740), 5-fluo
rouracil (NSC 19893), vinblastine (NSC 49842), vincristine
(NSC 67574), nitrogen mustard (NSC 762), and l,3-bis(2chloroethyl)-l-nitrosourea
(NSC 409962). Following 2
weeks of treatment,
estradiol-17fi levels were markedly
elevated by all compounds except testosterone mustard and
nitrogen mustard, which caused a decrease. Estrone levels
were elevated by methotrexate,
5-fluorouracil, vinblastine,
vincristine, nitrogen mustard, and 1,3-bis(2-chloroethyl)-l
nitrosourea, but were lowered by estradiol mustard. Proges
terone levels were elevated only by estradiol mustard and
testosterone mustard and were not affected by other corn
pounds. Prolactin surge during proestrus was suppressed by
phenesterin and methotrexate.
Luteinizing hormone levels
were lowered by methotrexate and nitrogen mustard. Es
trous cycles of rats treated with estradiol mustard were
arrested at proestrus, and the uterine and pituitary weights
of these rats markedly increased. Uterine weight loss was
significant following treatment with testosterone mustard,
5-fluorouracil, and nitrogen mustard. Thyroid weight was
reduced by all compounds except methotrexate and vinblas
tine. Significant increases in pituitary weights occurred
following treatment with all compounds except l,3-bis(2chloroethyl)-l-nitrosourea.
The effects on ovarian and adre
nal weights were minimal although significant by some
compounds. Thus, in addition to their direct antiturnor
effects, these agents also produce changes in endocrine
system which may be synergistic or antagonistic to the
chemotherapy of endocrine-responsive
neoplasms.
Many types ofneoplasms, both spontaneous and induced,
are known to arise in the various endocrine organs as well as
in the target tissues of hormones. The growth of tumors
arising in endocrine-responsive
tissues is frequently found to
be hormone dependent or at least hormone responsive.
Recent studies (9, 11) on gs antigen expression have
produced evidence suggesting that certain hormones may
also play a role in activating the oncogenic expression of
some RNA tumor virus genomes. While hormonal effects
are often associated with stimulation of tumor growth, an
inhibitory effect on tumor growth may also be exerted by
hormones (14, 24). The use of androgens and estrogens in
the therapy of human prostatic and mammary cancers are
classical examples of such effects.
Since nonhormonal chemotherapeutic
agents have been
found to inhibit various hormone responsive neoplasms also
(14, 24), it is a logical extrapolation
to assume that, in
addition to their direct effects on tumor cells, they may
exert significant effects on the endocrine system of treated
subjects. For example, depression of ovarian function has
been reported for myleran and N,N',N―-triethylenethio
phosphoramide
in addition to their antitumor activity (8,
20). However, relatively little information is available con
cerning the changes in endocrine organs, and especially in
serum hormonal levels, in response to treatment
with
chemotherapeutic
agents. Such information
is necessary
1 This
study
was
supported
by
Contract
NOI-CB-50006
from
the
actions
of
chemotherapeutic
agents
are
to
be
fully
Breast
Cancer Program Coordinating
Branch, Division of Cancer Biology and
Diagnosis, National Cancer Institute. An abstract of this study has been
published (15).
Received February 24, 1975; accepted April 14, 1975.
AUGUST
if
understood and exploited effectively in planning drug corn
binations and therapeutic
modalities to be used in the
therapy ofcancers arising in hormone-responsive
tissues.
As I facet of a research effort designed to determine the
chemotherapy
responsiveness of animal mammary tumor
models, 9 representative
anticancer
chemotherapeutic
agents were tested in female rats to determine their effects
on the estrous cycle, the endocrine organs, and the serum
levels of PRL,2 LH, E1, E3, and PRG. The results of these
tests are presented in this report.
2Theabbreviations
usedare:PRL, prolactin;LH, luteinizinghormone;
5-FU, 5-fluorouracil;
BCNU,
l,3-bis(2-chloroethyl)1-nitrosourea;
E,,
estrone; E,, estradiol-l7@;
PRG, progesterone;
ACTH, adrenocortico
tropic hormone.
1975
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research.
1975
E. Y. H. Kuo et a!.
MATERIALS AND METHODS
Experimental Animals. Forty-five ARS-Sprague-Dawley
stock female rats, 100 days of age, were used for the control
and for each compound tested. Animals were housed in an
environment with controlled light and dark cycles of 12 hr
and were maintained on a regular diet of Wayne Lab Blox
(Allied Mills Inc., Chicago, Ill.) and tap water ad !ibitum.
Upon arrival at this laboratory, rats were numbered and
allowed to acclimatize to the environment for I week before
being placed on test. Body weights were recorded 3 times
weekly, and animals showing signs of respiratory infection
or weight loss were excluded from the experiment.
Estrous Cycle Observation, Drug Treatment, and Serum
Collection
The estrous cycles of each rat were followed by daily
examination of its vaginal smear between 2:00 to 5:00 p.m.
for 10 days prior to the initiation of drug treatment. Rats
that did not exhibit regular cycling were excluded from the
experiment. Daily determination
of the estrous stage for
each rat was continued during the treatment period.
Chemotherapy was initiated on Day 11. Compounds were
administered in the morning over a 14-day period, either s.c.
or p.o., and either daily or 3 times weekly (Monday,
Wednesday, and Friday). On the last day of treatment,
between 2:00 and 5:00 p.m., following determination
of
estrous stages, all rats were sacrificed. In order to minimize
the effect of stress on hormonal levels, rats were gently
removed from the cage and quickly decapitated for blood
collection. Blood was allowed to clot at 4°for at least I hr
and then centrifuged to separate serum. Since the quantity
of serum obtainable
from each individual rat was not
sufficient for the simultaneous measurement of 5 hormones
Antimetabolites. (a) Methotrexate (NSC 740), N-[p-[(2,4diamine-6-pteridinyl)methyl]methylamino@benzoyl
glu
tamic acid, 0.2 mg/kg, 3 times weekly, p.o.; (b) 5-FU (NSC
19893), 25 mg/kg/day,
p.o.
Vinca Alkaloids.
(a) Vinblastine
(NSC 49842), yin
caleukoblastine
sulfate, 0.05 mg/kg/day,
s.c.; (b) vincris
tine (NSC 67574), leucocristine sulfate, 0.02 mg/kg/day,
s.c.
Alkylating Agents. (a) Nitrogen mustard (NSC 762),
methylbis(2-chloroethyl)amine,
or mechlorethamine
hydro
chloride, 0. 1 mg/kg/day,
s.c.; (b) BCNU (NSC 409962),
0.2 mg/kg/day,
s.c.
Radioimmunoassays of PRL and LH
The methods for radioiodination of rat PRL and LH, and
the double antibody radioimmunoassay
used in this study,
have been reported in detail elsewhere ( 16). Hormones and
antihormone
sera were kindly provided by the National
Institute of Arthritis and Metabolic Diseases as rat PRL
and rat LH radioimmunoassay
kits which included purified
hormone for radioiodination
(NIAMD-Rat
Prolactin-I-l
and NIAMD-Rat
LH-I-2), reference preparation to be used
for standards (NIAMD-Rat
Prolactin-RP-l
and NIAMD
Rat LH-RP-l)
and antihormone sera (NIAMD-Anti-Rat
Prolactin Serum-I and NIAMD-Anti-Rat
LH Serum-l).
Goat anti-rabbit
‘y-globulin, obtained from Antibodies,
Inc., Davis, Calif., was used as the 2nd antibody. Purified
hormones were radioiodinated with 1311in this laboratory.
Radioimmunoassays of Estrogens and Progesterone
To each 2-mI serum sample, 1000 cpm of tritiated E1, E2,
and PRG were added for recovery estimation. The serum
(PRL, LH, E1, E2, and PRG), the sera from 2 to 4 rats in was then extracted 3 times with 5 volumes of cold diethyl
the same estrous stage were pooled and stored at —20°. ether from a freshly opened can. The ether layer was
recovered, washed once with distilled water, and evaporated
Subsequently,
hormonal levels were determined on these
to dryness under a stream of nitrogen. The residue was
pools and their mean values were calculated.
dissolved in benzene:methanol
(9:1) and applied to Sepha
Immediately after exsanguination,
the pituitary, ovaries,
dcx
LH-20
microcolumns
for
chromatographic
separation
uterus, adrenals, and thyroids were removed from each rat
of the different steroids according to a modification of the
and examined for gross morphological changes, and weights
were recorded. The organ weights were then converted to procedure described by M ikhail et a!. ( 17) and by Murphy
(1 9). The
different
chromatographic
fractions
containing
mg/ 100 g body weight.
E1, E2, and PRG were dried down under nitrogen and
resuspended in absolute ethanol. E1, E3, and PRG were
CompoundsTested, Dose Levels, and Treatment Regimens3
quantitated
by radioimmunoassay
procedures
patterned
after the methods reported by Abraham (1), Knobil (13),
Steroid Alkylating Agents. (a) Estradiol mustard (NSC
and Abraham et a!. (2), respectively. The antiserum to E3
112259),
estra- I,3,5( I0)-triene-3, I7$-diol,
bis@p-[bis(2was kindly provided by Dr. B. V. Caldwell of Yale
chloroethyl)amino]phenyl$acetate,
5 mg/kg,
3 times
University School of Medicine, New Haven, Conn.
weekly, p.o.; (b) testosterone mustard (NSC I 12260), an
drost-5-enI 7-one, 3f3-hydroxy@p-[bis(2-ch1oroethyl)amino]phenyflacetate,
10 mg/kg, 3 times weekly, p.o.; (c)
RESULTS
phenesterin
(NSC
I04469) (cholest-5-en-3$-ol@p-[bis(2chloroethyl)aminoJphenyl@acetate,
10 mg/kg,
3 times
Summarized in Table 1 are the results showing the effect
weekly, p.o.
of chemotherapeutic
agents on the relative wet weights of
endocrine organs with respect to final body weight. The
effects of treatment on the estrous cycles and the serum
Biology and Diagnosis of the National Cancer Institute.
$ Chemotherapeutic
I976
agents
were
obtained
from
the
Division
of
Cancer
CANCER
RESEARCH
VOL. 35
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research.
@
;
Effects ofAntitumor
Agents on Endocrine System
Table I
Efftct of chemotherapeutic agents on body and endocrine organ weights
Organ weights were recorded at sacrifice following 2 weeks of treatment, as described in text. Each value
represents mean, or mean ±S.D. of 45 rats.
wt/ I00 g of final body wt
(mg)UterusOvaryThyroidPituitaryAdrenalControl
Test compoundFBW:IBWaOrgan
Estradiol
mustard
Testosterone
mustard
Phenesterin
Methotrexate
5-FU
Vinblastine
Vincristine
Nitrogen
mustard
BCNU1.02
0.97
±41.2
239.3 ±30.8°
±6.0
45.9 ±6.2
±17.5
22.4 ±9.3k'
±1.3
7.8 ±0.9°
±3.4
33.0 ±5.0―
0.97
150.2 ±31.8°
43.2 ±6.6
40.2 ±13.5°
5.3 ±0.8°
28.4 ±3.9
0.99
1.03
0.97
1.01
1.02
0.91
178.9 ±32.3
197.1 ±43.2c
161.8±36.lc
179.9 ±37.6
174.9 ±37.9
136.5±46.0°
43.0 ±5.3
69.1 ±16.5° 5.1 ±0.8°
49.7±5.1―
100.0±17.0― 5.9±0.7°
38.5 ±5.3°
21.9±5.2° 5.1 ±1.0―
44.1 ±5.3
81.9 ±14.3
5.5 ±0.9―
41.5 ±5•4c 66.0 ±17.4° 5.1 ±0.8°
51.4± 13.9° 5.0±0.8°
4l.0±5.8c
1.00178.6177.0±46.343.9 45.2±8.478.4
70.5±25.6°4.1 4.5±1.027.3
29.9 ±3.9°
29.9 ±3.2°
27.3±3.8
27.8 ±3.4
27.8 ±3.8
29.0±3.5c
30.7±7.6°
aRatioof finalbodyweightto initialbodyweight.
@50
@
S Significant
difference
(p
<
0.01)
from
the
control.
C Significant
difference
(p
<
0.05)
from
the
control.
final body weight to initial body weight reflect little change
in body weights of these animals as a result of treatment,
indicating little or no drug toxicity.
0
hi,,
116
@
[1
0
..-...‘.,.@‘.
.
.
...@.,.
....‘—‘
440
400
360
320
@
@
260
—200
180
20
80
40
240
220
200
I 80
I 60
F
@
@
@
@
40
120
00
80
@e0
40
20
@
L
PEMO
@
@
PEPVV ‘PEMO
d
@o
a@
U
W@
a
‘PEMO
PEMO
p@p@ â€P̃EMD
PEMO
‘PEMO
PEMO'
!
@-
1;;
i
Chart I . Effect of chemotherapeutic
agents on estrous cycle and serum
levels of prolactin and luteinizing hormone in the rat. P. E. M, and D,
proestrus, estrus, metestrus and diestrus, respectively. Numbers above
bars, number of serum pools obtained from rats at each estrous stage.
Hormonal levels of these pools were determined by radioimmunoassay
and
their mean values were plotted. ND, not determined.
hormonal
levels are illustrated
summary
of the results
in Charts
is also presented
I and 2. An overall
in Table
2.
Except in the case of nitrogen mustard treatment, which
caused a significant decrease in body weight, the ratios of
AUGUST
Estradiol Mustard (NSC 112259). Treatment with this
compound produced a significant increase in uterine, pitui
tary, and adrenal weights, and a marked decrease in thyroid
weight. No significant change in ovarian weight was ob
served. Examination of vaginal smears showed that all rats
failed to cycle and remained in proestrus during the latter
part of the treatment period. Radioimmunoassay
of serum
hormonal levels revealed an extremely high E2, a lowered
E1, and high PRL and PRG levels. No significant change
occurred in LH levels.
Testosterone Mustard (NSC 112260). Treatment with this
compound caused a mild decrease in relative uterine weight,
a marked decrease in thyroid weight, and a slight increase in
pituitary weight. Ovarian and adrenal weights were not
affected. The treated rats were able to proceed with their
estrous cycling. No significant changes occurred in serum
LH and PRG levels. In contrast to the very high E2:E1
ratios observed following administration
of estradiol mus
tard, treatment with testosterone
mustard resulted in a
lowered E2:E1 ratio. Serum E2 levels were lowered, and
serum E1 and PRG levels were increased above control
levels.
Phenesterin (NSC 104469). No significant changes in
ovarian and uterine weights were observed following the
administration
of this compound. There was, however, a
slight increase in adrenal and pituitary weights and a slight
decrease in thyroid weight. The number of rats in estrus
increased and that in metestrus decreased, suggesting a
prolongation in the duration of estrus. There were increases
both in serum E1 and E2 levels.
Methotrexate (NSC 740). Administration of methotrex
ate seemed to be stimulatory
to all endocrine organs
measured, causing a mild increase in the relative weights of
1975
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research.
I977
@
U
E. Y. H. Kuo et a!.
the ovaries, uterus, thyroid, adrenals, and pituitary. The
number of rats at proestrus increased, but the serum PRL
levels at proestrus and the serum LH levels at all estrous
stages
were
lower
than
those
of
the
control
group.
No
change was seen in the serum PRG level, but both E1 and E3
were
considerably
higher
than
the levels
found
in the control
group.
5-FU (NSC 19893). Moderate decreases in ovarian and
uterine weights and a very marked decrease in thyroid
weight were observed following treatment with 5-FU. Both
E1 and E2 levels were several times higher in these treated
animals than in those in the control group. As a result of the
higher E1 and E2 levels, greater numbers of rats were at
proestrus or estrous stages on the day of sacrifice.
220
200
ieo
@ieo
,g120
@l40
@1@@
g eo
L
40
20
@
@
I
I
.
k°
4200
200
.
,
•____,
I80
proestrous
I leo
@
120
@I00
60
lii
40
20
leo
40
30
20
PEMD
‘PEMD
‘PEMO
â€P̃EMD
‘PEMO ‘
MO'
,.tan.,
z
@
and
Vincristine
(NSC
67574).
stage.
However,
the number
of rats
reaching
Nitrogen Mustard (NSC 762). Administration
10
@
@
49842)
proestrus and estrus increased, compared with the control
group. Vincristine, on the other hand, caused a 2- to 5-fold
increase in serum E1 at all estrous stages and a 4- to 10-fold
increase in serum E2 at proestrus and estrus. Despite such
marked increases in serum E1 and E2 levels, uterine growth
and the PRL surge at proestrus were not stimulated, and
there was no increase in ovarian weight. Similar results were
also observed in the group treated with 5-FU.
140
@
(NSC
hiftifir
@eo
U
Vinblastine
The only organ affected by vinblastine was the pituitary,
which showed a mild weight increase. Vincristine, on the
other hand, caused a mild decrease in thyroid weight and a
slight increase in pituitary weight. Vinblastine caused a 2- to
5-fold increase in serum E1 and a 3- to 5-fold increase in
serum E2 during metestrus-diestrus
stages and, interest
ingly, caused decreases in both serum E1 and E2 levels at
Wloo
a
- ‘-c―L'
- P.t@i)
-
U
z
ft iI@
4
U)
z
>
-I
9-
@, 5
Chart 2. Effect of chemotherapeutic
agents on serum levels of estrone,
estradiol-17fl and progesterone
in the rat. P, E. M, and D, proestrus,
estrus, metestrus, and diestrus, respectively. Each plotted value represents
the mean hormonal level of the serum pools obtained from rats at each
estrous stage. The number of serum pools for each estrous stage is
indicated in Chart I . ND, not determined.
of this
prototype alkylating agent caused marked decreases in
uterine and thyroid weights, an effect similar to that
produced by the testosterone mustard. In addition, it caused
a slight decrease in ovarian weight and a slight increase in
adrenal weight. Serum PRL and PRG levels and the cycling
pattern of the treated animals were apparently not affected.
Serum LH and E2 levels were markedly lowered and the
serum E1 level was greatly elevated.
BCNU (NSC 409962). Treatment with this alkylating
agent caused only a slight decrease in thyroid weight and a
slight increase in adrenal weight. However, its effect on
serum estrogen levels was quite marked: E1 was elevated 2-
Table 2
Summary of the effects of chemotherapeutic agents on serum hormonal levels and endocrine organ weights
wtE2E1PRGPRL°LHUterusOvaryThyroidPituitaryAdrenalEstradiol
Serumhormonal
levelOrgan
mustard
Testosterone
mustard
Phenesterin
Methotrexate
5-FU
Vinblastine
Vincristine
Nitrogen
mustard
BCNU+°
a Only
° +
the
and
0
0
+
+
0
+
+
+
+
+
+
+
+
—
+
0
0
0
0
0
0
+—
++
00
proestrous
surge
— , hormonal
levels
no significant
I978
—
difference
ofserum
and
0
wt/unit
0
—
body
—
+
0
—
0
0
0
—
+
+
—
—
+
+
+
+
+
0
0
0
0
0
0
0
—
—
—
+
0
0
0
0
+
—
—
+
0
0
0
—
—
—
—
+
+
0+
00
0—
-+
0+
+
00
PRL
organ
weights
level
ofeach
significantly
treated
group
higher
was
or
lower,
compared
respectively,
with
that
ofthe
than
the
control.
control.
0,
from the control.
CANCER
RESEARCH
VOL. 35
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research.
Effects ofAntitumor
@
to 5-fold, and E2 was elevated 2- to 10-fold during the van
ous estnous stages, compared with the serum estrogen levels
in the control group. As a result, the number of rats in es
trus was double that of the control group on the day of
sacrifice. The serum levels of LH and PRG were not sig
nificantly affected, but the PRL surge at proestrus was
lower than that of the control. These results are rather
similar to those produced by 5-FU, which is an anti
metabolite, and are in contrast to the results produced by
another alkylating agent, nitrogen mustard, which caused
only E1 increase.
DISCUSSION
Table 2 summarizes
the effects of chemothenapeutic
agents on serum hormonal levels and organ weights. Of the
9 compounds
tested,
7 increased
serum
E2 levels,
6 elevated
serum E1 levels, 8 stimulated pituitary weights, 7 markedly
decreased thyroid weights, and 5 increased adrenal weights.
These results clearly indicate that chemotherapeutic
agents,
both hormonal and nonhormonal in nature, produce various
degrees of changes in the endocrine system of treated
subjects.
It is of
interest
to
note
that
all
tested
compounds
except
testosterone mustard caused increases in serum levels of
either E2, E1, or both. Judging from the lack of increase in
ovarian weight following treatment with most compounds,
it can
be speculated
that
the
increases
in serum
estrogen
levels were probably not the results of increased ovarian
secretion of estrogens but, rather, were due to a generalized
decrease in estrogen utilization by target tissues, resulting in
the accumulation
of circulating estrogens. This view is
supported by the absence of uterotropic effect following
treatment
with most compounds,
despite the increased
serum levels of estrogens, which are known to stimulate
uterine growth. In fact, treatment with 5-FU suppressed
uterine weight while serum levels of both E1 and E2 were
elevated. These results suggest that one of the anticancer
activities of these compounds may lie in their ability to
interfere with the uptake of estrogens by target tissues. A
recent work by Everson et a!. (6) has clearly shown that
estradiol mustard inhibits the binding of tnitiated E2 to its
receptors
in rat uterine
cytosol.
Two exceptions were estradiol mustard and methotrex
ate, which stimulated uterine growth. Being an estrogen
analog itself, estradiol mustard apparently exerted a direct
uterotrophic effect (23), resulting in an increase in uterine
weight while ovarian weight remained unchanged. Thus,
methotrexate
was the only compound that produced a
normal pattern of stimulatory effects, namely, increased
ovarian
weight,
elevated
serum
estrogen
levels,
increased
uterine weight, and a suppressed serum LH level.
Of the endocrine organs examined, the greatest change in
organ weight following treatment
was observed in the
thyroid. For example, administration
of estradiol mustard
and 5-FU reduced the thyroid weights (mg/kg body weight)
to 22.4 ±9.3 and 21.9 ±5.2, respectively, compared with
78.4
± 17.5
thyroid
AUGUST
for
weights
the
control
group.
were effected
Substantial
decreases
in
by 7 of the 9 compounds
Agents on Endocrine System
tested. Interestingly,
methotrexate
was, again, the only
compound that exerted a stimulatory effect on the thyroid.
Although serum levels of thyroid hormones were not
measured in this study, it was unlikely that the treated
animals could have maintained the same concentrations of
thyroid hormones in their blood after their thyroids were
reduced to less than one-third of their normal sizes. Recent
in vitro (22, 25) studies have shown that thyroid secretion
from
mouse
thyro
glands
in response
to thyroid-stimu
lating hormone was inhibited by colchicine and vinblastine.
This observation was confirmed by in vivo studies (4) that
showed that vinblastine caused an inhibition of the thyroid
stimulating hormone-induced endocytosis ofthe thyroid and
the release of thyroid hormone.
Hypothyroid condition has been found to increase the
incidence
of 7, 12-dimethylbenzanthracene-induced
rat
mammary tumors (5, 21). It has also been found to be
associated with massive virginal breast hypertrophy (10)
and breast cancer in humans (3). In estrogen-primed
rats,
thyroidectomy induced a marked stimulation of mammary
development which was completely suppressed by replace
ment doses ofthyroxin (18). In view ofthese findings, it may
he of value to attempt to determine, experimentally
and
clinically, whether the thyroid suppression produced by
these drugs reduces their anti-mammary
tumor efficacy,
and if so, whether such undesirable effect can be overcome
by the addition of thyroxine to the treatment regimen to
prevent possible mammary
stimulation
due to thyroid
suppression.
Although small in magnitude,
adrenal weights were
stimulated by 5 compounds. It is not known whether these
weight increases were due to direct drug effect, the effect of
stress, or to the elevated serum estrogen levels. In this
respect, estrogen has been clearly shown to stimulate
ACTH release from the pituitary and a simultaneous
increase in adrenal weight (12). Also unclear is whether the
significant increases in pituitary weights following treat
ments with 8 of the 9 compounds were direct drug effects or
the result of hormonal interaction. A practical concern is
whether these pituitary weight increases were accompanied
by an increased ACTH release and subsequent stimulation
on adrenals, resulting in elevated levels of glucocorticoid
hormones. This concern is prompted by a recent report (7)
that glucocorticoids
enhanced the replication in vitro of
mouse mammary tumor virus. The adrenal stimulation
observed in the present study suggests that ACTH release
may have been stimulated by some compounds. However,
further studies that measure the changes in ACTH and
glucocorticoids
are necessary to verify such therapeutic
effects.
REFERENCES
I. Abraham, G. E. Solid-phase Radioimmunoassay
of Estradiol-l7beta.
J. Clin. Endocrinol. Metab., 29: 866—870, 1969.
2. Abraham, G. E., Swerdloff, R., Tulchinsky, D., and Odell, W. D.
Radioimmunoassay
of Plasma Progesterone.
J. Clin. Endocrinol.
Metab., 32:619—624, 1971.
1975
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research.
I979
E. Y. H. Kuo et a!.
3. Bogardus, G. M., and Finley, J. W. Breast Cancer and Thyroid
and B. V. Caldwell (eds.), Immunologic Methods in Steroid Deter
mination, Chap. 6, pp. 113-126. New York: Appleton-Century
Diseases. Surgery, 49: 461—468, 1961.
Crofts, 1970.
4. Ekholm, R., Ericson, L. E., Josefsson, J. 0., and Melander, A. In vivo
Action of Vinblastine
on Thyroid Ultrastructure
and Hormone
Secretion. Endocrinology, 94: 641 -649, 1974.
5. Eskin, B. A. Iodine Metabolism and Breast Cancer. Trans. N. Y.
Acad. Sci.,32:911—947,
1970.
14. Krakoff, I. H. The Present Status of Cancer Chemotherapy.
Med.
Clin. N. Am., 55: 683—701, 1971.
15. Kuo, E. Y. H., Esber, H. J., Taylor, D. J., Schaeppi, U., and Bogden,
6. Everson, R. B., Turnell, R. W., Wittliff, J. L., and Hall, T. C.
Agents. Proc. Am. Assoc. Cancer Res., 15: 77, 1974.
Kuo, E. Y. H., and Gala, R. R. Radioimmunoassay
of Rat Prolactin
Comparing Prolactin Obtained from Anterior Pituitary Organ Culture
with that Distributed
by the National
Institute of Arthritis and
Metabolic Diseases. Biochim. Biophys. Acta, 264: 462—471, 1972.
Mikhail, G., Wu, C. H., Ferin, M., and Vande Wide, R. L.
Radioimmunoassay
of Plasma Estrone and Estradiol. Steroids, 15:
333—352,
1970.
Mittra, I. Mammotropic
Effect of Prolactin Enhanced by Thyroidec
tomy. Nature, 248: 525—526, 1974.
Murphy, B. E. “Sephadex―
Column Chromatography
as an Adjunct
to Competitive Protein Binding Assays of Steroids. Nature New Biol.,
232:21—24,
1971.
Oliverio, V. T., and Zubrod, C. G. Clinical Pharmacology
of the
Effective Antitumor Drugs. Ann. Rev. Pharmacol., 5: 335—356, 1965.
Shellabarger,
C. J. Hypothyroidism
and DMBA Rat Mammary
Carcinogenesis.
Proc. Am. Assoc. Cancer Res., 10: 313, 1969.
Temple, R., Williams, J. A., Wilber, J. F., and Wolff, J. Colchicine
and Hormone Secretion.
Biochem. Biophys. Res. Commun.,
46:
1454—1461,
1972.
Vollmer, E. P., Taylor, D. J., Masnyk, I. J., Cooney, D., Stevenson,
Estradiol Mustard (NSC-l 12259) and Phenester (NSC-l 16785): Pos
sible Mediation
of Action by Estrogen Binding Protein. Cancer
A. E. Hormonal and Endocrine Organ Response to Chemotherapeutic
16.
Chemotherapy Rept., 58: 353—357,1974.
7. Fine, D. L., Plowman, J. K., Kelley, S. P., Arthur, L. 0., and Hillman,
E. A. Enhanced Production of Mouse Mammary Tumor Virus in
Dexamethasone-treated,
5-Iododeoxyuridine-stimulated
17.
Mammary
Tumor Cell Cultures. J. NatI. Cancer Inst., 52: 1881—1886,1974.
8. Galton,
D. A. G. The Use of Myleran and Similar Agents in Chronic
18.
Leukemias. Advan. Cancer Res., 4: 73—1
12, 1956.
9. Hellman, A., and Fowler, A. K. Hormone-activated Expression of the 19.
C-type RNA Tumor Virus Genome. Nature New Biol., 233: 142—144,
1971.
10. Hollingsworth, D. R., and Archer, R. Massive Virginal Breast 20.
Hypertrophy at Puberty. Am. J. Diseases Children, 125: 293—295,
1973.
11. Huebner,
21.
R. J., Kelloff, G. J., Sarma,
P. 5., Lane, W. T., Turner,
H.
C., Gilden, R. V., Oroszlan, S., Meier, H., Myers, D. D., and Peters,
R. L. Group-specific Antigen Expression during Embryogenesis of the
Genome of the C-type RNA Tumor Virus: Implications for Ontogene
sis and Oncogenesis. Proc. Natl. Acad. Sci. U. S., 67: 366—376,1970.
12. Kitay, J. I. Effects ofthe Gonadal Hormones on ACTH Secretion. in:
L. Martini and A. Pecile (tds.), Hormonal Steroids, Biochemistry,
Pharmacology and Therapeutics, Vol. 2, pp. 317—324.New York:
Academic Press, Inc., 1965.
13. Knobil, E. A Comment in the Discussion of: G. Mikhail, H. W.
Chung, M. Ferin, and R. L. Vande Wide. Radioimmunoassay of
Plasma Estrogens: Use of Polymerized Antibodies. In: F. G. Peron
1980
22.
23.
B., and Piczak, C. Estradiol Mustard (NSC-l 12259). Clinical Bro
chure. Cancer Chemother. Rept., 4 (Part 3): 121-140, 1973.
24. Wade, R. Hormones. In: R. J. Schnitzer and F. Hawking (eds.),
Experimental Chemotherapy.
Chemotherapy
of Neoplastic Diseases,
Vol. 2, pp. 133—331.
New York: Academic Press, Inc., 1967.
25. Williams, J. A., and Wolff, J. Possible Role of Microtubules
in
Thyroid Secretion. Proc. NatI. Acad. Sci. U. S., 67: 1901—1908, 1970.
CANCER
RESEARCH
VOL. 35
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research.
Effects of Cancer Chemotherapeutic Agents on Endocrine
Organs and Serum Levels of Estrogens, Progesterone,
Prolactin, and Luteinizing Hormone
Eric Y. H. Kuo, Henry J. Esber, D. Jane Taylor, et al.
Cancer Res 1975;35:1975-1980.
Updated version
E-mail alerts
Reprints and
Subscriptions
Permissions
Access the most recent version of this article at:
http://cancerres.aacrjournals.org/content/35/8/1975
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Department at [email protected].
To request permission to re-use all or part of this article, contact the AACR Publications
Department at [email protected].
Downloaded from cancerres.aacrjournals.org on June 16, 2017. © 1975 American Association for Cancer Research.