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Pharmacological Research, Vol . 25, Supplement 1, 1992 EFFECTS OF MELATONIN ADMINISTRATION ON TUMOR SPREAD IN MICE BEARING LEWIS LUNG CARCINOMA . V . Rapozzi, L . Perissin, S . Zorzet, T . Giraldi • .
Institute of Pharmacology, University of Trieste and
Institute of
(4 )
Biology, University of Udine . Key words : tumor, metastasis, stress, melatonin . It is know that environmental and psychological factors may influence tumor and
incidence and
immune system .
progression in The
pineal
laboratory animals
gland and
its hormone
via
neuroendocrine
melatonin have
been
shown to possess an important role in mediating the influence on the immunity exerted by psychological and environmental stressor stimulus . Melatonin appears
involved also in various biological functions among which the
regulation mitosis
of
(1) .
gonadal,
adrenal
and thyroid
activity,
sleep
and
cellular
In this connection melatonin has been studied for its possible
implication in the control of neoplastic growth . The aim of
this work was
that to determine the effects of melatonin administration in mice bearing Lewis lung carcinoma subjected to the stressor paradigm, spatial disorientation . The animal used are young BD2F1 female mice, which were kept 5 per cage in order progression .
to avoid the The cages were
effects of
overcrowding or isolation on tumor
placed in a
protected housing
for
two
weeks
before tumor inoculation to allow the animals to recover from the stress of shipment and to adapt the cabinet were 12/12 the cages ; described
them to the housing conditions . (light/dark h/h)
The light cycles in
with an intensity of
2100 lux
(2) . The protected housing consisted of a cabinet containing the
animal cages with laminar air flow,
minimizing acoustic,
visual communication among the cages,
and also with events outside of
cabinet . The rooms .
in
tumor transplantation and evaluation were performed as already
cabinet were contained in
a room distant
Spatial disorientation was applied to the
olfactory and
from
animals
the
other animal
by spinning
the
cages at 45 rpm for 10 min every hour from time of tumor inoculation until sacrifice . These experimental conditions have
been already described
(2) .
Melatonin was administered in drinking water to avoid the stress of parenteral drug administration that has been shown increase metastasis formation (2),
at dosages of 1 .25 mg/Kg/day
from tumor
(dissolved in 1 :500 ml ethanol :tap water)
inoculation to sacrifice
on day 22 .
Since this hormone in
humans and animals shows a physiologically circadian rhythm with a nocturnal peak and a diurnal abolition of melatonin
its plasmatic and urinary
levels,
administration was performed only in the dark hours (from
1043-6618/92/2510071-02/$03 .00/0
the 8 .00
© 1992 The Italian Pharmacological Society
72
Pharmacological Research, Vol. 25, Supplement 1, 1992 p .m .
to 8 .00 a .m .) The results obtained indicated that the application of
spatial diso-
rientation causes a significant increase of primary tumor growth and metastasis formation . Melatonin administration produces a significant effect in animals not subjected to
spatial
disorientation, increases
the cure rate
from 0/10 to 5/10 and significantly reduces metastasis weight . Table 1 . Effects of melatonin administration on primary tumor growth and metastasis formation in mice bearing Lewis lung carcinoma subjected to spatial disorientation (SD) . PRIMARY SD
MELATONIN
(MG)
+ +
+
METASTASIS
TUMOR
TUMOR WEIGHT NUMBER
WEIGHT (MG)
654±132 8
10±2c
36± 7d,e
0/109
479±192b
6±1
14± 5d,f
5/10 , h 0/10 0/10'
1416±303 8
21±4c
72±11e
1411±237b
12±2
55±13f
+
FREE
Each value is the mean±S .E . of groups of 10 mice . Means marked with the same letter are significantly different, grouped data, ( e-f ) and Fisher's exact test ( 9, b), p(0 .05 .
t-test for
These results are in agreement with those already reported by different investigators suggesting a protective role of melatonin against metastasis formation in tumor bearing animals . pinealectomized hamsters (3)
These observations were made in
or in normal mice implanted with B16 melanoma
(4) . At the same time the results presented sure to stress of
laboratory animals are
significantly modifies These findings indicate ing melatonin,
the
effect
of
indicate that levels an
exogenous
of expo-
important variable, melatonin
which
administration .
the complexity of neuroendocrine circuits, includ-
involved in stress responses and encourage further investi-
gations on the participation of this hormone in neuroimmunomodulation in relation to tumor metastasis . REFERENCES 1 . Relkin R, The pineal gland_ New York : Elsevier Biomedical, 1983 :311 2 . Giraldi T, Perissin L, Zorzet S, Piccini P, Rapozzi V . Effects of stress on tumor growth and metastasis in mice bearing Lewis lung carcinoma . Eur J Cancer Clin Oncol 1989 ; 25 :1583-88 3 . Das Gupta TK, Terz J . Influence of pinealgland on the growth and spread of melanoma in the hamster . Cancer Res 1967 ; 27 :1306-11 4 . Fraschini F, Scaglione F, Franco P, Demartini G, Lucini V, Stankov B . Melatonin and immunity . Acta Oncol 1990 ; 29 :775-6