Beatriz Martins Tavares Murta Jother Soares Machado Mateus Zaparoli Vítor Carvalho Lara Eddie Fernando Candido Murta
R eview
The re lationship of host immune ce lls, cytokine and
nitric oxide production to tumor ce lls in ovarian carcinoma
Discipline of Pharmacology, Department of Biological Sciences, Discipline of Gynecology and
Obstetrics, Faculdade de Medicina do Triângulo Mineiro, Uberaba, Brazil
REVIEW
Tumor-associated mononuclear cells (TAMs)
So lid tumo rs co nsist o f malig nant cells and stro ma . Ma lig na nt c ells elic it stro ma fo rma tio n
and this is essential fo r neo plasia g ro wth.1 Many
tumo rs o f epithelia l o rig in c o nta in, in the tumo r stro ma , a sig nific a nt numb er o f infiltra ting ho st le uko c yte s, e sp e c ia lly ma c ro p ha g e s a nd
lympho c ytes.2 Also , these c ells o b ta ined fro m
ne o p la stic e ffusio ns a re e xtre me ly use ful in evaluating the interactio ns between immune and c a nc e r c e lls in the tumo r mic ro e nviro nme nt.3 Phe no typ ic stud ie s (b y flo w c yto me try) a nd func tio na l stud ie s o f the so -c a lle d tumo r-infiltra ting leuko c ytes (rec o vered fro m tumo r) o r tumo r-a sso c ia te d le uko c yte s (re c o ve re d fro m ma lig na nt e ffusio ns) ha ve d e te c te d no
differenc es b etween these c ells,3 ,4 whic h will b e
re fe rre d to he re a s tumo r-a sso c ia te d mo no nuc lea r c ells (TAMs).
In te rms o f c ha ra c te riz a tio n o f the leuko c yte infiltra te, o va ria n c a nc er is o ne o f the
mo st e xte nsive ly stud ie d huma n tumo rs.5
Immuno histo chemistry analysis o f tissue sectio ns has sho wn that the cells present in larg e numbers a re ma inly ma c ro pha g es a nd T c ells.2 ,6 B c ells,
ABSTRACT
Aim s: This brief review fo cuses o n the current understanding o f the co mplex relatio nship o f tumo r-asso ciated mo no nuclear cells (TAMs) with neo plastic cells, summariz ing their immuno lo g ical efficiency, cyto kine pro file and pro ductio n o f nitric o xide (N O ) in the tumo r
micro enviro nment, with current insig hts o n ho w this mig ht affect tumo r g ro wth.
Da ta source: Data was o btained thro ug h Medline fro m articles indexed during the last 1 0 years. The main key wo rds used in the research were: cancer, o varian cancer, cyto kine, nitric o xide (N O ), mo no nuclear cell, lympho cyte, macro phag e.
Selection of studies a nd da ta collection: 3 0 studies were reviewed, which co ntained data reg arding the pro ductio n o f cyto kines and N O by TAMs o r malig nant cells, and tried to establish a co rrelatio n between these mediato rs and tumo r g ro wth, especially in o varian carcino ma.
Da ta sum m a ry : TAMs co nsist mainly o f macro phag es and T lympho cytes which present lo wer pro liferative indices and cyto to xicity co mpared to auto lo g o us blo o d mo no cytes, altho ug h they are able to release vario us cyto kines. The pro file o f cyto kine expressio n co uld help to explain bo th the immuno lo g ical impairment o bserved in patients with advanced carcino ma diseases and the po tential o f TAMs to exert antitumo r activity, which makes these cells an attractive targ et fo r therapeutic interventio n. N O is also pro duced in the tumo r micro enviro nment. Several repo rts in animals sug g est a tumo ricidal ro le fo r N O , but in human tumo rs its ro le has no t been well-established and may chang e during tumo r pro g ressio n.
na tura l kille r (N K) c e lls a nd ma st c e lls a re present in lo w numb ers. N eutro phils a re la rg ely c o nfined to b lo o d vessels a nd eo sino phils a re seen o ccasio nally. In g eneral, the infiltrating cell density is hig her in the stro ma tha n in the tumo r c o mpa rtment.2 In perito nea l o r pleura l effusio ns seco ndary to cancers at different sites, including o va ria n c a rc ino ma , c e lls c o nsist ma inly o f T ly mp ho c y te s, b ut N K c e lls, B c e lls a nd
macro phag es are also present.3 It has also been
repo rted tha t neutro phils a re freq uently fo und in the a sc ites o f o va ria n c a rc ino ma .5
Immunological efficiency of TAMs
It is no t kno wn whether TAMs a re a c ell p o p ula tio n tha t p a rtic ip a te s in the immune respo nse a g a inst the tumo r, o r whether these c ells mig ht even enha nc e the develo pment o f
the tumo r.7 In this c o ntext, it is kno wn tha t the
recruited leuko cytes can bo th reco g niz e and kill ma lig na nt c e lls a nd e sta b lish a n immune memo ry a g a inst them o r pro duc e fa c to rs tha t help tumo r g ro wth a nd va sc ula riz a tio n thro ug h
paracrine lo o ps.8 The co ncept o f a macro phag e
b a la nc e wa s intro duc ed b y Ma nto va ni et a l.9
to encapsulate the no tio n that macro phag es may a id o r inhib it tumo r g ro wth a c c o rding to their sta te o f a c tiva tio n.
In a study o f 2 5 patients with g yneco lo g ical tumo rs, o f who m 1 5 had o varian carcino ma, the auto lo g o us peripheral blo o d mo no nuclear cells (PBMCs) differed fro m TAM subset po pulatio ns in having a significantly higher po tential to pro liferate in re spo nse to mito g e n stimulus a nd a lso in presenting hig her cyto to xicity.7 Ag reeing with this data, TAMs o btained fro m perito neal o r pleural effusio ns seco ndary to cancer at different sites had a lo wer pro liferative respo nse to mito g ens than auto lo g o us PBMCs, which in turn was lo wer than that o f co ntro l PBMCs, indicating a functio nal immuno lo g ic a l imp a irme nt in p a tie nts w ith
advanced carcino ma disease.3
A no the r ind ic a to r o f the immune sta te is the p a tte rn o f c yto kine re le a se b y TA M s. Mo st o f the a va ila b le d a ta w a s o b ta ine d fro m a d va nc e d o va ria n c a rc ino ma . In a re c e nt
s tud y, i t w a s f o un d th a t th e c ulture d sup e rna ta nts o f mito g e n-stimula te d TA M s p ro d uc e d le ss IL-1
α
a ndβ
, TN F-α
, IL-4 a nd IL-1 0 , c o mp a re d to tho se o f a uto lo g o us a nd c o ntro l PBM C s, a s a sse sse d b y the ELISA te st.3 In a simila r stud y, IL-4 w a s the ma jo r c yto kine e xp re sse d b y TA M s, w hile IFN -γ
p ro d uc tio n w a s p re d o mina nt in PBM C s.7 The a na lysis o f c yto kine e xp re ssio n b y re ve rse tra nsc rip ta se p o lyme ra se c ha in re a c tio n (RT-PC R) s h o w e d th a t TA M s h a d re d uc e d e xp re ssio n o f g e ne s fo r IL-2 , IFN -γ
a nd IL-4 , a nd inve rse ly, ha d inc re a se d IL-1 0 g e ne e xp re ssio n re la tive to no rma l PBM C s.4 Ta ke n to g e the r, the se re sults sug g e st tha t the inc o mp le te a c tiva tio n o f TA M s in vivo ma y b e d ue to the a c c umula tio n o f Th2 c e lls inste a d o f Th1 c e lls, a nd it is p la usib le tha t the inc re a se d IL-1 0 c o ntrib ute s to d o w nw a rd s re g ula tio n o f the Th1 c yto kine s.But the ro le o f TAMs studied to date varies c o nsidera b ly, even in o va ria n c a rc ino ma . In a study o f a dva nc ed o va ria n c a rc ino ma , TAMs p ro d uc e d a p p re c ia b le a mo unts o f IL-6 a nd sp o nta ne o usly re le a se d sig nific a ntly hig he r a mo unts o f IL-8 , c o mp a re d to PBM C s.5 In patients with o varian o r breast cancer, cyto to xic T c ell c ultures, iso la ted fro m tumo rs a nd then further stimula ted with a uto lo g o us tumo r c ells, lysed these c ells a nd a lso sec reted c yto kines suc h a s TN F-
α
, IFN -γ
a nd G M -C SF.1 0 In a pro spec tive study o f 1 7 o va ria n c a rc ino ma s, it wa s o b served tha t pa tients in rela pse ha d a sig nific a nt re d uc tio n in TA M s, w hic h w e re una b le to respo nd to the tumo r a s evidenc ed b y the c o rrela tio n b etween tumo r g ro wth a nd a dec rea sed numb er o f infiltra ting c ells.6These differenc es in c ellula r c o mpo sitio n a nd the va ria b le p ro g no stic sig nific a nc e o f leuko c yte s tha t infiltra te ma ny huma n tumo rs sug g est tha t different types o f intera c tio ns a re po ssib le b etween tumo r a nd ho st c ells, po ssib ly re sulting in he te ro g e ne o us re spo nse s.8 Sinc e TAMs are lo cated at the tumo r-ho st interface and ha ve the po tentia l to exert a nti-tumo r a c tivity, these c ells ma y c o nstitute a n a ttra c tive ta rg et
fo r thera peutic interventio n.5
The role of cytokine expression in the tumor
Altho ug h the ro le o f infiltra ting c e lls in malig nant tumo rs is co ntro versial, a likely stimulus fo r the ir pre se nc e is the lo c a l pro duc tio n o f chemo kines, so that the leuko cyte co ntent o f a
tumo r may depend o n the expressed cyto kines.2
In this co ntext, a variety o f human and murine tumo r cells pro duce mo no cyte chemo attractant facto rs and there is a co rrelatio n between the amo unt o f activity in cultured supernatants and the number o f TAMs, when these cells pro duce tumo rs in vivo .1 1 Several lines o f evidence sug g est that mo no cyte chemo attractant pro tein-1 (MCP-1 ) is an impo rtant determinant o f macro phag e
infiltratio n into tumo rs (review9). The presence o f
messeng er RN A fo r MCP-1 in o varian carcino ma was first demo nstrated by an in situ hybridizatio n
technique,1 1 and this study also demo nstrated
the e x p re ssio n o f c he mo kine s suc h a s
macro phag e inflammato ry pro tein-1 (MIP-1
α
),MIP-1
β
and RAN TES activity (reg ulatio n upo na c tiva tio n: no rma l T c e ll e xp re ssio n a nd
stimula tio n) b y these tumo rs.2 Furthermo re, a
direct to po g raphical asso ciatio n was o bserved between the number o f chemo kine-expressing cells and the leuko cyte infiltrate at the
epithelial-stro ma interface.1 1
In g eneral, the majo r co mpo nents o f TAMs ha ve b een desc rib ed a s c ells resemb ling Th0 c e lls, i.e . pro duc ing b o th Th1 - a nd Th2 -type c yto kines, o r with a g ra dua l shift fro m Th1 to Th2 c ells o c c urring during pro g ressive tumo r g ro wth.3 The sec retio n o f Th1 -like c yto kines, a s o p p o se d to Th2 , c o uld p o te ntia lly furthe r enha nc e the endo g eno us immune respo nse to o va ria n c a nc e r.1 0 A na ly sis o f c y to kine e xpre ssio n using RT-PC R te c hniq ue s o n to ta l RN A iso la ted fro m o va ria n c a rc ino ma sho wed
tha t the ma jo rity expressed TG F-
β
a nd IL-1 0 ,with a b senc e o f expressio n o f IFN -
γ
. Ha lf o fthe se tumo rs e xp re sse d G M -C SF a nd IL-8 ,6 w hic h ha s a lso b e e n d e sc rib e d in vitro .8 In a c c o rda nc e with this, hig her c o nc entra tio ns o f IL-1 0 ha ve b e e n de mo nstra te d in ne o pla stic effusio ns seco ndary to cancers at different sites, inc luding o va ria n c a rc ino ma a nd, surprising ly, hig her IFN -
γ
c o mpa red to a uto lo g o us serum.3 Itis kno w n tha t IL-1 0 stro ng ly inhib its the
pro duc tio n o f TN F-
α
a ndβ
, G MCSF a nd IFN-γ
b y periphera l b lo o d mo no c ytes.6The d iffe re nc e s in the e xp re ssio n o f c yto kine s de sc rib e d in the lite ra ture ma y b e re la te d to histo lo g ic a l ty p e s o f o va ria n carcino ma analyzed in each study. Fo r example,
TN F-
α
a nd IL-2 a re g enera lly desc rib ed a s no tb eing c o nsistently detec ted in tho se tumo rs, in c o ntra st to IL-1 0 a nd G M-CSF.6 The a na lysis o f 1 3 c a ses o f o va ria n c a rc ino ma s sho wed tha t in o nly fo ur c a se s w e re c e lls e xp re ssing
messeng er RN A fo r TN F-
α
a nd IL-2 o b served,a number co nsiderably lo wer than that o bserved in infla mma to ry c o nditio ns suc h a s sa lping itis
o r in no rma l periphera l lympho id tissue.1 2 The
g ene fo r TN F wa s studied in b io psies o f huma n e p ithe lia l o va ria n c a nc e r a nd a p o sitive c o rrela tio n wa s fo und b etween TN F expressio n a nd tumo r g ra d e , sug g e sting tha t TN F
pro duc tio n ma y enha nc e tumo r develo pment.1 3
O va ria n c a rc ino ma c e lls p ro d uc e c yto kines tha t a ttra c t mo no c ytes a nd pro mo te their surviva l; TAMs in turn pro duc e c yto kines which can stimulate cancer cell g ro wth. So there is a n a mb iva lent rela tio nship b etween tumo r c e lls a nd TAMs. In the a b se nc e o f e ffe c tive thera peutic interventio n, evidenc e sug g ests tha t the b a la nc e is shifted in fa vo r o f the tumo r.1
A role for NO in tumor biology
N itric o x id e (N O ) is a n e sse ntia l p hysio lo g ic a l sig na ling mo le c ule me d ia ting va rio us c ell func tio ns, inc luding the c yto to xic / c yto sta tic effec ts o f the immune system a g a inst d e b ilita ting fa c to rs like infe c tio n a nd tumo r
(review1 4). But, when pro duced fo r a lo ng perio d
a nd in hig h c o nc entra tio ns, a n exc ess o f N O c o uld da ma g e DN A lea ding to g ene muta tio ns a nd c a nc er.1 5
Se ve ra l huma n c a nc e rs a re a sso c ia te d w ith c hro nic vira l, b a c te ria l a nd p a ra sitic infec tio ns, with N O fo rma tio n b eing eleva ted in these infec tio ns.1 6 Also , mo st o f the c ellula r c o mp o ne nts o f the tumo r ma ss (tumo r c e lls themselves a nd the immune c ells infiltra te) ha ve
The expressio n o f N O synthase (N O S) in tumo rs pro vo kes the questio n abo ut a physio lo g ical ro le fo r tumo r-a sso c ia ted N O pro duc tio n.
Severa l repo rts sug g est a tumo ric ida l ro le fo r N O in vivo . A c hro nic inhib itio n o f N O synthe sis w ith N -mo no me thyl-L-a rg inine (L-N MA) re sulte d in inc re a se d tumo r g ro wth a nd d e la y e d immune re c o g nitio n in mic e , implic a ting e ndo g e no us N O in the impa ire d a b ility o f tumo r c e lls to pro life ra te.1 8 Mo re o ve r, the da ily intra pe rito ne a l a dministra tio n o f L-N MA prevented the tumo ric ida l a c tivity in mic e w hic h w e re p re ino c ula te d w ith b a c illus C a lme tte -G ué rin (BC G ) a nd sub se q ue ntly tra nsp la nte d w ith syng e nic o r xe no g e nic o va ria n tumo r c e lls. Sinc e it ha s b e e n d e mo nstra te d tha t N O me d ia te s the BC G -induc e d ho st re sista nc e to tumo r g ra fts in mic e , it is mo st like ly tha t N O a c c o unts fo r the tumo ric id a l a c tivity.1 9 A lso in mic e , the administratio n o f cyto kine-stimulated tumo r cells c a use d a tw o -fo ld inc re a se in sub c uta ne o us tumo r g ro w th a nd e xp e rime nta l p ulmo na ry me ta sta se s, in re la tio n to c o ntro l c e lls. N -mo no me thyl-L-a rg inine a c e ta te re duc e d tu-mo r siz e a nd the numb e r o f lung me ta sta se s to the c o ntro l le ve ls, sug g e sting tha t tumo r c e ll N O pro duc tio n wa s re spo nsib le fo r this e ffe c t.2 0
In huma n tumo rs the ro le o f N O ha s no t b een esta b lished. N O ha s b een repo rted a s b e ing diminishe d o r a b se nt in pre ma lig na nt lesio ns and tumo rs o f the larg e intestine,1 4 while, c o nve rse ly, a n inc re a se d le ve l o f N O S e xpre ssio n a nd/ o r a c tivity w a s o b se rve d in huma n g ynec o lo g ic a l tumo rs, a nd this fa c t wa s inve rse ly a sso c ia te d w ith the d iffe re ntia tio n g ra de o f the tumo r.2 1 In o va ria n c a nc er, hig h levels o f N O S a c tivity were detec ted, while the enz yme a c tivity wa s b elo w detec ta b le levels in g ynec o lo g ic a l tissue fro m no n-c a nc er pa tients. In a d d itio n, the immuno re a c tive p ro te ins in which N O S activity was detected were lo calized to the tumo r c ells.2 2
S inc e c y to kine s a nd hy p o x ia c a n syne rg istic a lly ind uc e N O S e xp re ssio n, the pre ma lig na nt a nd ma lig na nt tumo r tissue ma y e sta b lish susta ine d N O pro duc tio n in a va rie ty
o f tumo r c e lls. Ho w e ve r, the e ffe c t o f N O p ro d uc tio n in tumo r b io lo g y ma y c ha ng e
during tumo r pro g re ssio n.2 1 This hypo the sis is
suppo rted b y da ta investig a ting the ro le o f N O in c a nc e r me ta sta sis. Afte r in vitro inc ub a tio n w ith c yto kine s o r LPS, no n-me ta sta tic c e lls exhib ited a hig h level o f induc ib le N O S a c tivity a nd N O pro duc tio n, whe re a s me ta sta tic c e lls d id no t. The tra nsfe c tio n o f tumo r c e lls pro duc e d fa st-g ro wing a nd hig hly me ta sta tic tumo rs, whe re a s func tio na l iN O S-tra nsfe c te d c e lls p ro d uc e d slo w -g ro w ing a nd no n-me ta sta tic tumo rs in syng e nic o r nude mic e . The se d a ta ind ic a te tha t N O d e c re a se d surviva l o f tumo r c e lls in the c irc ula tio n a nd inhib ite d tissue inva sio n.2 3
A hyp o the sis ha s b e e n p ut fo rw a rd sug g esting that lo ss o f N O fro m a bio lo g ical cell co uld enable it to evade cell-cycle arrest and terminal differentiatio n, resulting in a premalignant cell o r predispo sed cell. A lo ss o f N O fro m a malig nant cell co uld result in unco ntro lled cellular divisio n. Sinc e pe rsiste nt va so dila ta tio n is a specific feature in tumo r vasculature and in the surro unding tissue, N O generated by the vascular endo thelium in the pro ximity o f o r within the tumo r, under the co ntro l o f a lo cal g ro wth facto r, co uld re g ula te the tumo r b lo o d flo w via vaso relaxatio n.1 4 ,1 7 In additio n, the ro le o f N O in
ang io g enesis is well do cumented.1 7
Cancer g ro wth can be stimulated as well as inhibited by the immune system. The intratumo r macro phag e arg inine metabo lism is a mo lecular explanatio n fo r the dual ability o f the immune system to inhibit o r stimulate tumo r g ro wth. It has been pro po sed that arg inine metabo lism in the tumo r bed yielding citrulline and N O favo rs tumo r rejectio n, whereas pro ductio n o f o rnithine and
urea co uld pro mo te tumo r g ro wth.2 4
Interactions between cytokines and nitric oxide
O ne o f the first re c o g niz e d na tura l mechanisms fo r reg ulating N O synthesis was IL4 . W hen macro phag es were activated with IFN
-γ
a nd a lo w d o se o f LPS, the y p ro d uc e d sig nificant amo unts o f N O and expressed hig h levels o f N O S. This pro ductio n and expressio nwere inhibited in a do se-dependent manner by preincubating the cells with IL-4 . IL-1 0 and TG Fb can also inhiFbit N O synthesis. In co ntrast, IFN
-γ
a nd TN F-α
, o c c up ying the ir re sp e c tive recepto rs, transmit a series o f sig nals leading tothe expressio n o f N O S and the synthesis o f N O .2 5
In vitro , human MCP-1 was able to inhibit the pro ductio n o f N O by a macro phag e cell line, sug g esting that tumo r-derived MCP-1 is likely to re p re se nt a me c ha nism fo r c o ntro lling N O -mediated macro phag e cyto to xicity, and fo r the recruitment and co nco mitant partial functio nal
deactivatio n o f TAMs.2 6
A d va nc e d ne o p la sia ha s lo ng b e e n a sso c ia te d with de fe c tive c a pa c ity to mo unt respo nses to inflammato ry stimuli. Thus, a balance between chemo tactic and inhibito ry cyto kines may
reg ulate infiltrate in tissues, including neo plasms.1
In this co ntext, it is kno wn that in mice IL-8 and
TNF-
α
cause defective neutro phil recruitment whenadministered in the sistemic circulatio n,2 7 -2 9 and
the pro ductio n o f N O is invo lved in this inhibito ry
activity.3 0 This o bservatio n raises the po ssibility
that cyto kines, leaking fro m advanced tumo rs, play a ro le in systemic defects o f inflammatio n and
immunity asso ciated with neo plasia.1
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Bea triz M a rtins Ta va res M urta - Asso ciate Pro fesso r o f the Disc ipline o f Pha rma c o lo g y, Depa rtment o f
Bio lo g ic a l Sc ienc es
Jother Soa res M a cha do - Underg raduate student o f the Fa c ulty o f Medic ine o f Triâ ng ulo Mineiro
M a teus Z a pa roli - Underg raduate student o f the Faculty o f Medic ine o f Triâ ng ulo Mineiro
V ítor Ca rva lho La ra - Underg raduate student o f the Fa c ulty o f Medic ine o f Triâ ng ulo Mineiro
RESUMO
O bjetivos: Analisar a co mplexa relação entre as células mo no nucleares asso ciadas ao tumo r (TAMs) e as células neo plásicas, sendo resumido s sua co mpetência imuno ló g ica, perfil da pro dução de cito cinas e de ó xido nítrico (N O ) no micro ambiente tumo ral, co m aspecto s atuais de co mo a pro dução desses mediado res po deria afetar o crescimento tumo ral.
O rigem dos da dos: O s dado s fo ram o btido s de artig o s indexado s através da rede Medline durante o s último s 1 0 ano s. As palavras-chave utiliz adas na pesquisa fo ram basicamente: câncer, carcino ma o variano , cito cina, ó xido nítrico , células mo no nucleares, linfó cito , macró fag o . Seleçã o dos estudos e coleta dos da dos: Fo ram revisto s 3 0 trabalho s co ntendo dado s relacio nado s à pro dução de cito cinas e N O po r TAMs e/ o u células neo plásicas e que tentaram estabelecer uma co rrelação entre a pro dução desses mediado res e o crescimento tumo ral, particularmente no carcino ma o variano . Resum o dos da dos: As TAMs co nsistem principalmente de macró fag o s e linfó cito s T que apresentam baixo índice pro liferativo e baixa cito to xicidade co mparada ao s mo nó cito s autó lo g o s do sang ue, embo ra sejam capaz es de liberar várias cito cinas. O perfil da expressão de cito cinas po deria ajudar a explicar tanto a deficiência imuno ló g ica o bservada em pacientes co m carcino ma em fase avançada co mo também o po tencial das TAMs em exercer atividade antitumo ral, o que to rna essas células um alvo para intervenção terapêutica. Além das cito cinas, o N O também é pro duz ido no micro ambiente tumo ral. Várias o bservaçõ es em animais sug erem um papel tumo ricida para o N O , mas em tumo res humano s seu papel não fo i estabelecido po dendo ser alterado durante a pro g ressão do tumo r.
Eddie Ferna ndo Ca ndido M urta - Asso ciate Pro fesso r o f the Disc ipline o f G ynec o lo g y a nd O b stetric s, Fa c ulty o f Medic ine o f Triâ ng ulo Mineiro , Ub era b a , MG , Bra z il
Sao Paulo Med J/Rev Paul Med 1999; 117(2):87-92.
Sources of Funding: N o t dec la red
Conflict of interest: N o t dec la red
La st received: 1 6 July 1 9 9 8
Accepted: 1 O cto ber 1 9 9 8
Address for correspondence:
Bea triz Ma rtins Ta va res Murta Disciplina de Farmaco lo g ia,
Departamento de Ciências Bio ló g ica s, Fa c ulda de de Medic ina do Triâ ng ulo Mineiro Pra ç a Ma no el Terra , 3 3 0
