71

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

Effects of melatonin administration on tumor spread in mice bearing Lewis lung carcinoma.

71 Pharmacological Research, Vol . 25, Supplement 1, 1992 EFFECTS OF MELATONIN ADMINISTRATION ON TUMOR SPREAD IN MICE BEARING LEWIS LUNG CARCINOMA ...
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