Cancer Epidemiol Biomarkers Prev 1991 de Flora 95 9

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1991;1:95-99.Cancer Epidemiol Biomarkers Prev

S De Flora, G Bronzetti and J H Weisburger Antimutagenesis and Anticarcinogenesis.Third International Conference on Mechanisms of

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Vol. 1, 95 9 9 N ovem b er/D ecem ber 1991 C anc er E pidem io lo gy, B io ma rk ers P rev en tio n 95

M eeting R eport

Third International C onference on M echanism s ofA ntim utagenesis and A nticarcinogenesis1

Silv io De Flo ra , G io rg io B ro nzetti, andJ oh n H . Weis bu rg er2

Istituto di Igiene e M edic ina P reventiva, U nivers il {224} di G enova, 1-16132

G enoa, Italy [S . DeF.]; Islituto d: M utagenesi e Diffe renziam enlo del

C NR , 1-56124 P isa, Italy [C. B .]; and Am erican Health Foundation,

Valhalla, New Y ork 10595 [1. H . W .]

Abstrac t

Th is co nferen ce, a ttend ed by scientis ts from 27cou ntries , fo cused on th e m ost recent advan cesin thefie ld o f antim utag enesis an d anticarc in og enesis .Particu lar em ph asis w as given to the m ech anis ticap pro ach, w h ich is believed to be an essen tialp rereq uis ite fo r a safer and m o re effec tiveim plem enta tio n o f ch em o preven tio n o f cancer an d ofm utatio n-re la ted d iseases . The arrang em en t of the sixreg ular sess ion s basica lly fo llow ed and u pd ated thedeta iled class ifica tio n o f m echan ism s of in hib ito rs o fm utagen esis an d carc ino gen esis p rop osed by S. D eFlora an d C . Ram el M u tat. R es.,202 : 285-306, 1988),coverin g b oth extracellu lar an d cellu lar m ech anism sin volved in the preven tio n of m utatio ns an d can cerin itia tion , as w ell as in the m o du la tio n of la ter s tag es ofth e carc ino gen esis p ro cess . In ad dition , a w o rksho pw as devo ted to m eth od olo gical asp ects con cernin g them od ula tion o f th e gen otoxic and carc in og enicresponse .

The p resent repo rt covers the m ain th em es o fo verview lectures o r research co m mun icatio nsp resented b y m ore than 60 speakers . M o stp resenta tio ns w ere m u lti-autho red , as th e resu lt o fco llabo ra tive stu dies , in severa l cases at th ein tern atio nal level, bu t on ly the n am es o f sp eakers w illb e g iv en .

R ec eived 7/3 /91.

, IC M AA -IlI, held M ay 5-10 , 1991, in II Ciocco Lucca), Italy , w as thethird in a series of tniannual conferences. IC M A A-I look place on O ctober

6-10, 1985, in Lawrence, K ansas , and IC M AA -Il on Decem ber4-9, 1988,

in O hito, Japan. The conference proceedings of IC M AA -I and ICM AA -II

have been published by P lenum P ress, N ew Y ork and London, in 1986D . M . S hankel, P . E . H artm an, T. K ada, and A . H ollaender, eds .) and

1990 Y . K uroda, D. M . S hankel, and M . D . W aters, eds.), respectively.

IC M AA -IV is scheduled for early Septem ber 1994 in B anff A lberta,

C anada) under the cha irm anship of R . C. von B orstel.

G . B nonzetti was the chairperson of ICM AA -lII, and S . De Flora acted as

the chairperson of the S cientific Program C om m ittee. The proceedings

of all regular sess ions will be published in a P lenum P ress volum e, and

the papers presented in the W orkshop on the A ssessm ent of A ntim uta-

genicily and Anticanc inogenic ily. End-points and S ystem s will be pub-

lished in a special issue ofM utation R esearch.

2 To whom requests for reprints should be addressed, at A m erican Health

Foundation, Dana R oad, Valhalla, N Y 10595.

M echan is tic A pp ro aches to An tim utagen esisa n d A n t ic a rc in o g en e s is

Session 1 included three in troductory lec tures on genera lm echanism s. Silvio D c Flora Institute of H ygiene andPreventive M edic ine , U niversity of G enoa, Ita ly) h igh-lighted the role of antim utagenesis and anticarc inogene-sis in the prim ary prevention of m utations and cancer, asre la ted to other in tervention stra tegies . H e discussed theproblem s involved in chem oprevention and stressed theim portance of a m echanistic approach. Based on anupdated classifica tion , he provided an analysis of m ech-anism s of inhib itors explo itab le for preventive purposes.R . C . von Bonste l D epartm ent of G enetics, U niversity ofAlberta , E dm onton, Alberta , Canada) defined the m ajorm echanism s involved in the orig in of spontaneous m u-tations, i.e. the three R s necom bination , replica tion ,and repair) in D NA m etabolism . Further protectionagainst spontaneous m utations m ay be afforded by inhib-iting in tracellu lar free radicals and form ation of alkyla tingagents, as w ell as DN A depunm nations and im balances ofnucleotide pools . Severa l inhib itors are know n on, m oreoften , suspected to w ork through m ultip le m echanism s,and Luigi M . D c Luca Laboratory of C ellu lar C arcinogen-esis and Tum or Prom otion , N ational C ancer Institu te ,Bethesda , M D) em phasized the ability of re tinoids to

profoundly affect tum onigenesis and discussed the un-denly ing bio logical m echanism s, with specia l referenceto their ro le in the m aintenance of norm al cell d iffenen-tia tion . This property involves the nuclear netinoic acidreceptors, which belong to the superfam ily of stenoid /thyroid receptors. The three in troductory lec turesstressed the possib le occurrence of adverse effects ofinhib itors, under certa in conditions, and the double-edged nature of severa l m echanism s.

Inh ib ition o f M u tag enesis and C arcino g en esis b yE xtra ce llu la r M ec ha nis ms

An interesting approach to cancer chem oprevention isto in tercept harm ful agents when they are still in extra-cellu lar spaces . A prom ising m ethod, reported by Helm utBantsch In ternational Agency for Research on Cancer,Lyon, France), is to prevent the endogenous form ationof N -nitnoso com pounds from nitrite and am ino precun-sons in the acid ic gastric environm ent but a lso in othersites a t neutra l pH , due to cata lysis by bacteria l enzym es.Inhib itors , such as vitam ins C and E, plant phenols , andcom plex m ixtures in the die t, w ere review ed along w ithan evaluation of their m echanism s and efficacy, a lsosupported by epidem iological evidence and by studiesin hum ans. The protective m echanism of die tary fib trwhich has been associa ted w ith a lower risk of coloncancer and breast cancer in anim al m odels and hum ans,was review ed by John H . W eisbungen Am erican H ealth

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96 M eet in g R e p ort

Foundation, Valhalla , N Y). Soluble fibers are metabolizedby bacteria l enzymes in the intestine , where they caninhibit colon carcinogens, whereas insoluble fibers in-crease stool size , diluting tumor initia tors and promotersof e ither exogenous or endogenous source . Two coon-dinated lectures by D elbert M . Shankel (D epartment of

M icrobiology, University of Kansas, Lawrence, KS) andPhilip E . H antman (Johns H opkins University, Baltimore ,M D) described the mechanisms responsible for the cx-tracellular interception of mutagens and carcinogens.This type of defense , often provided by biomoleculesfrom a die tary source , may be due to physica l barriers,chemical reactions, on enzyme-cata lyzed processes. Ki-yomi Kikugawa (Tokyo C ollege of Pharmacy, Tokyo, Ja-pan) reported on the ability of prote ins and their diges-tion products to act as scavengers of nitrite , e ither bydeamination or by favoring formation of nonmutagenicderivatives.

M o d u la t io n o f M etab o lis m an d B lo ck in g o fReac tiv e Sp ec ies

A varie ty of mechanisms of inhibition can be involved inthe intracellular environment. Session 3 dealt with cyto-plasmic processes affecting the metabolic activation ondetoxifica tion of mutagens/carcinogens, on blocking ne-active species, thereby preventing their interaction withcritica l cell macromolecules. Thomas Kenslen (JohnsH opkins U niversity) focused on inducers of e lectrophiledetoxication enzymes, such as the gluta thione S-transfer-ases, U D P-glucunonyl transfenases, and N AD (P )H :quin-one reductase . Chemoprevention can be achieved inmany target tissues by administering monofunctional in-ducers, such as dithiolthiones, which enhance Phase IIenzymes without stimula ting cytochnome P-450 activi-ties. P eter M old {233}us(D epartm ent of T oxicology, Kanolin-ska Institute , S tockholm, Sweden) pointed out the pro-

tective properties of G SH 3 and of the enzymes involved.A number of G SH analogues and precursors have beenstudied. The most important is N -acetylcyste ine , whicheffectively evokes gluta thione biosynthesis, protectsagainst drug-induced toxicity, and displays a broad arrayof antimutagenic and anticarcinogenic properties. M i-chad G . Simic (N ational Institute of Standards and Tech-nology, G aithensbung, M D) stressed the importance ofreduction of oxidative damage in the overa ll process ofcancer prevention and delineated the mechanism ofaction of antioxidants, a lso depending on their redoxpotentia l and cell localiza tion. E lectron transfer and H -atom transfer from phenolic antioxidants to oxidizingintermedia tes were evaluated in experimenta l systems.

These introductory lectures were followed by pnes-enta tions of original research data . Four of them dealtwith the protective effects and mechanisms of sulfurcompounds, especia lly thiols. G iovanni Brambilla (Insti-tute of Pharmacology, U niversity of G enoa, G enoa, Ita ly)investigated the ability of thiols to reduce DN A fragmen-ta tion, as assessed by viscosimetry, induced in ra t livenby low doses of N -nitrosodimethylammne. Disulfinam was

3 The abbreviations used are: G S H, glutathione ; P P, protein phosphatases;

IQ , 2 -a mino-3 -m elhylim ida zo[4 ,5 -fJquinoline ; G lu-P -1 , 2 -a mino-6 -m elh-yldipynido-[1,2-a:3 ,2-d]im idazole ; T rp-P -2, 3-am mno-1-m ethyl-5H -pyn-

ido[4,3-b]indole; TIM P , tissue inhibitor of metalloproteinase; BHA, bu-

l yl at ed h yd ro xy a ni so le .

the most effective of 10 thiols. R oberto Barale (Depart-ment of Evolutionary Biology, U niversity of Fernana, Fennara , Ita ly) reported the ability of N -acetylcysteine toinhibit bacteria l mutagenicity as well as the enhancementof sister chromatid exchanges in cultured human lym-phocytes induced by diese l exhausts. Y asushi Yamazoe

(D epartment of Pharmacology, Keio U niversity, Tokyo,Japan) investigated the ability of thiols to modula te theactivity of acetyltransferase and sulfotransferase involvedin ra t liven metabolism of the heterocyclic anylammne G lu-P-i D avid J. M eyer (C R C M olecular Toxicology R esearchG roup, U niversity C ollege and M iddlesex School of M cd-icine , London, England) demonstra ted the induction ofG SH S-tnansfenase subunits in the liven cytosol of ra ts fedwith the anticancinogenic drug oltipnaz . Subunits lb and3 seemed to detoxify afla toxin oxide , and subunits7 7detoxified benzo(a)pyrene-7 ,8-diol-9 ,1 0-oxide by G SHconjugation. However, the analogy with tumon-promot-ing agents triggering similar mechanisms was also pointedout. Three presenta tions reported on the protective ef-fects of antioxidants in different experimenta l systems.M asao H irose (First D epartment of Pathology, N agoyaCity U niversity, N agoya, Japan) described extensive can-cinogenicity studies in ra ts with BH A and severa l natura llyoccurring antioxidants, displaying organ-specific activity,especia lly via stimula tion of cell prolifera tion. Using theoxygen radical genera ting system of xanthine/xanthineoxidase , D iana Anderson (BIBRA Toxicology Interna-tional, C anshalton, England) observed that vitamin C wasmore efficient than vitamin E in inhibiting malformationsin whole ra t embryo cultures and detachment of germcells cocultiva ted with Sertoli ce lls. M ichael J. P lewa(Institute for Environmenta l S tudies, U niversity of Illinoisa t U rbana-C hampaign, IL) explored the mechanisms ne-sponsible for blocking the activation of aromatic aminesby pe noxida se inhibitors, such a s die thyldithioca rba ma te .Cultured tobacco cell suspensions were used as theactivating system and bacteria as the genetic indicatororganism.

M o d u la t io n o f DN A R ep air an d C o n t ro l o fG en e E xp res sio n

Session 4 was devoted to intnanuclean mechanisms in-volved in D N A replica tion and repair in the control ofgene expression in mammalian cells, prokaryotes, andoncogenic viruses, David A. Boothman (D epartment ofR adia tion O ncology, U niversity of M ichigan, Ann Arbor,M l) introduced the complex subject of modula tion ofD N A repair. Inhibition of DN A repair, which prefenen-tia lly occurs in areas of the genome undergoing highlevels of transcription, leads to a varie ty of consequencesfor damaged mammalian cells. A possible use of D N Arepair inhibitors is to prevent cancinogenesis by enhanc-ing le thality in damaged cells, as investigated with fi-lapachone, a D NA repair inhibitor and topoisomenase Imodula tor. C urtis C . Harris (Laboratory of Human C an-cinogenesis, N ational C ancer Institute) dealt with mod-ula ting effects on oncogenes, tumor suppressor genes,and antimetastasis genes, with emphasis on suppressorgenes, their mechanisms, and their involvement in hu-man cancinogenesis. The possibility of modula ting geneexpression with the goal of cancer prevention is sup-ported by evidence that somatic cell hybrids betweennormal human bronchia l epithelia l ce lls and lung carci-noma lines have a finite life span. The control of the



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C an ce r E pi de m io lo g y B io m ar ke rs P re ve nt io n 97

expression of human papillomavirus in neoplasia wasaddressed by Joseph A. D iPaolo (Laboratory of Biology,National C ancer Institute), who generated immorta lizedcell lines derived from human epithelia l cervica l ce llsconta ining integra ted, rearranged, and transcniptionallyactive human papillomavinus genomes. Assays with trans-

forming growth factor 3 l and f.2, a- a nd - y- in te rfe ro n,and leukonegulin established that hepatitis B virus geneexpression is differentia lly regula ted by specific cytokmnesproduced by cervical epithelia or by leukocytes infiltrat-ing cervica l dysplasia and carcinom a.

The modula tion of D NA repair in bacteria was pre-sented by Takehiko N ohmi (National Institutes of H y-gienic Sciences, Tokyo, Japan), who suggested that thesamAB and the umuD C51 operons play an important rolein U V and chemical mutagenesis inS alm onella typhim u-rium and by D ietnich Schulte-Fnohlinde (M ax-Planck In-stitu t f {2 52 }rtna hle nke mie , M {2 52 }lhe im a .d. R uhn, G erm any),who showed that misrepain leading to dele tion mutationin Escherichia co/i-transforming plasmids is strongly influ-enced by base sequences vicinal to the restriction site .

G eorge Kopsidas (D epartment of M icrobiology, La TrobeU niversity, M elbourne , Austra lia) found that the frame-shift mutagenesis of 9-aminoacnidine in S.typhimuriuminvolving intercala tion of its planar molecule into D N A,is modula ted by the type of carbon source in the me-dium, with a significant depression by glucose . FrancescoFeo (Institute of G enera l Pathology, University of Sassani,Sassani, Ita ly) reported on the chemopneventive effectsof S -adenosyl-L-m ethionine in ra t hepatocancm nogenesismodels and on the mechanisms involved. S-Adenosyl-L-methionine can counteract hypomethyla tion and over-expression of c Ha r as c Ki r as and c-myc appearingearly during tumor promotion and persisting in neoplasticnodules. H inoshi Kasai (N ational C ancer C enter R esearchInstitute , Tokyo, Japan) spoke on an international collab-onative study (involving Japan, Korea , France , and theUnited S ta tes) on one of the major products of D N A basedamage, 8-hydnoxyguanine , induced by oxygen radicals,in turn stemming from the action of diverse carcinogenson radia tion. C hlorogenic acid extracted from plants in-hibited its in vitro formation due to lipid peroxide . For-mation of 8-hydroxyguanine in the liven of -y-inradia tedmice decreased with time, due to repair by a specificendonuclease , that has been purified. Sahdu D evakiN andan (D epartment of Physiology and Pharmacology,Texas A & M U niversity) observed that netinoic acidincreased c-Ha-ras mR NA levels in a ra t hepatoma cellline , as well as in ra t aortic smooth muscle cells trea tedin vitro w ith b en zo (a )p yre ne .

M ec h an is m s o f In h ib it io n o f Tu m or Pro m o tio nP r o g re s s io n I nv a s io n a n d M e t as t as e s

Peter Cenutti (D epartment of C arcinogenesis, Swiss Insti-tute for Experimenta l Cancer R esearch, Epalinges, Swit-zenland) described the fine balance of the multiple com-ponents of the antioxidant defense , as a response togrowth promotion by oxidants. The oxidativ stress trig-gens (patho)physiological reactions playing a role in in-flammation, fibrosis, and tumonigenesis. The importanceof cellular antioxidant defenses was demonstra ted by thedecrease in inducibility of the protooncogene c-los intransfectants of mouse epidenmal cells overproducingsupenoxide dismutase on cata lase . An overview of inhib-tons of tumor promotion and progression in the multi-

stage mouse skin model was presented by Barbour S .W arren (U niversity of Texas S ystem C ancer C enter,Smithville , TX). A varie ty of mechanisms may be associ-a ted with the inhibition of tumor promotion by differentagents, e .g., scavenging of free radicals, antiprolifera tiveor antim nflamm atory effects, altera tions of cell differentia-

tion, prote in processing or calcium regula tion, blockingof prostaglandmn synthesis or ornithine decarboxylaseinduction, cytotoxic effects, e tc. Free radical scavengingmay be involved in prevention of tumor progression, asshown by the protective effect from the topical applica-tion of G SH . C harles W . Boone (ChemopreventionBranch, National C ancer Institute) described the intra-epithelia l neoplasia (or dysplasia) which precedes inva-sive epithelia l cancer. C ancer chemopreventive agentscan inhibit the progression ofthe intraepithelia l neoplasiaby two basic mechanisms, i.e. mutagen blocking andprolifera tion suppression. W hatever the mechanism, in-hibitons are expected to prolong the la tency period be-fore the appearance of cancer.

These introductory lectures were followed by re-

search reports. Ann R . Kennedy (D epartment of R adia-tion O ncology, University of P ennsylvania , Philadelphia ,PA) dealt with the anticarcinogenic effects of proteaseinhibitors, especia lly the soybean-derived Bowman-Birkinhibitors. M ultiple mechanisms are involved, includingthe normaliza tion of some carcinogen-induced effects,such as increased levels of proteolytic activities, geneamplifica tion, on c-myc expression. M inako N agao (N a-tional Cancer C enter Research Institute , Tokyo, Japan)highlighted the role of PP involved in the signal transduc-tion of malignant transformation, as shown, e .g., by anenhanced mRN A expression ofPP-2Ace in hepatocellularcarcinomas induced by carcinogens produced duringcooking. O kadaic acid, a specific inhibitor of PP-i andPP-2 , yie lded fla ttened forms of activated c-rafandretTtransformants of N IH 3T3 cells. M asami S uganuma (Na-tional Cancer C enter R esearch Institute , Tokyo, Japan)discussed the antipromoting properties of natura l com-pounds, i.e. sarcophytol A, epigallocatechin gallate , andcryptoponic acids D and E, isola ted from a soft cora l,green tea, and a fungus, respectively, which partly act bysuppressing oxyradicals. She proposed a combination ofvarious antitumon promoters for cancer chemopreven-tion. Patnizia H nelia (D epartment of Pharmacology, U ni-versity of Bologna, Bologna, Ita ly) reported on the effectsof a- and fl-interferons on benzo(a)pyrene metabolismand clastogenicity. Treatment of mice with interferonsresults in a temporary depression of P -450 isozymes andof hepatic oxidative drug metabolism , as well as ofbenzo(a)pynene-induced clastogenicity in bone marrowcells. V ladimir Knutovskikh (International Agency for R e-search on C ancer, Lyon, France) observed that functionalgap junctional intercellular communications and celladhesion molecules are necessary for efficient tumorsuppression and anticarcinogenesis. Adniana Albini (N a-tional Institute for C ancer R esearch, G enoa, Ita ly) usedan in v itr o reconstituted basement membrane as a modelto study tumor cell invasion and metastases. Invasion ofbasement membranes can be inhibited by severa l com-pounds such as TIM P-2, a member of the tissue inhibitorof meta lloproteinase (TIM P) family, inhibitors of collagen-ase IV , and a cyste ine-conta ining synthetic peptide .M oreover, invasiveness of oncogene-transfonmed cellsw s i nh ib it ed b y i nt er fe ro ns



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C an c er E p id e m io lo gy B io m arkers P re ve n tio n 99

technical inadequacies. G iongio Bronzetti C NR Institu teof M utagenesis and D ifferentia tion , P isa , Ita ly) d iscussedshort-term test system s in yeasts for assessing the anti-m utagenic ity of com pounds reacting with m utagens orin terfering w ith cellu lar functions, and gave exam ples ofm echanism s of inhib itors of physica l or chem ical m uta-

gens in stra in D 7 ofS accha rom yce s ce re visia e YukiakiKuroda Azabu U niversity, Sagam ihana, Japan) discussedthe m ethodologies used for assessing antim utagenic ef-fec ts, w ith specia l reference to the evaluation of 6-thio-guanine-resistan t m utations in C hinese ham ster V 79 cells,and using pre- on posttrea tm ent techniques. Erich G eb-hart Institu te of Hum an G enetics, U nivers ity Enlangen-N urnberg , N urnberg , G erm any) reviewed in deta il testsystem s evaluating antic lastogenicity in cultured m am -m alian cells. The results are considerably influenced bythe experim enta l conditions as w ell as by the end pointinvestigated, e .g . chrom osom e aberra tions on sister chro-m atid e xc han ge s.

The second part of the w orkshop was devoted toinvivo test system s. Claes R am el D epartm ent of G enetic

and Cellu lar Toxicology, U nivers ity of Stockholm , Stock-holm , Sw eden) discussed the m odula tion of genotoxicityin rosophila tes t system s, in particu lar the som atic m u-ta tion and recom bination tests S M A RT), a useful m odelfor e lucidating the m echanism s of inhib ition of recom -binogenic and m utagenic effec ts. Lester M itschen Dc-partm ent of M edicinal Chem istry , Kansas U niversity,Law rence, KS) com m ented on m ethodologies for isola t-ing and screening antim utagens in pure form from higherplants . An interesting system , according to G eorge S.Bailey D epartm ent of Food Science and Technology,O regon Sta te U nivers ity, C orvallis, O R ), is fish , such asra inbow trout, s ince as m any as 10,000 anim als can beused, thereby provid ing high sta tis tical pow er as to pro-tective on adverse effects tow ard various end points b iochem ical indices, carcinogen-D NA adducts, neoplas-

tic lesions). Charles W . B oone C hem opreventionBranch, National Cancer Institu te) described chem icallyinduced autochthonous tum or system s to assess the ef-ficacy of candidate chem opreventive agents , nam elychem ically induced m ouse skin papillom as, ra t m am m aryadenocarcinom a, ham ster tracheal squam ous cell carci-

nom a and lung adenocarcinom a, ra t or m ouse colonadenocarcinom a, and m ouse bladder carcinom a.

Four reports dealt w ith the m onitoring of m utationor cancer protective effects in hum ans. M ortim er L. M en-delsohn Lawrence Liverm ore N ational Laboratory, Liv-erm ore , CA ) discussed the estim ation of som atic m uta-tional effects , feasib le in hum ans for five assay-genecom binations. H e com m ented on the hypoxanthm nephosphonibosyltransferase and glycophonin A assays forevaluating antim utagenic effects in hum ans, w hich w ereused to find either a reduction of background levels or am odula tion of response to know n m utagens. M ichael G .Sim ic N ational Institu te of Standards and Technology,G aithensburg , M D ) proposed the applica tion of urinarybiom ankers for evaluating the protective effects of an-

tioxidants in the die t or as chem opreventive additives.These m arkers involve detection in unines of thym idm neglycol and 8-hydroxydeoxyguanosine , tw o products of.O H radical reactions w ith DN A bases. M iriam P . R osin

Cell B iology U nit, S im on Fraser U niversity, Burnaby,British C olum bia , C anada) discussed the evaluation ofantic lastogenicity in hum ans, especia lly the m icronucleustest on exfolia ted cells in individuals in popula tions ate levated risk for cancer. This technique w as particu larlyuseful as an in term edia te end point during trea tm entw ith chem opreventive agents. C harles W . Boone re-v iew ed chem oprevention tria ls by the National C ancerInstitu te C hem oprevention Branch. Third-generationtria ls , now in progress, evaluate the chem oprevention ofcancer a t various sites sk in , breast, lung, colon, andcervix) in high-risk individuals.

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Cancer Epidemiol Biomarkers Prev 1991 de Flora 95 9