Document kmo7e4q0yJKZLDK4GvygMqxqD

CANCEROCENE W1KKUNC VON K V \ STSTO FF-FO LI E N 553 ' Cancerogene Wirkung von Kunststoff-Folien' . Voo Hksuann Dai'Ctaer und Dif.tsicii Schmmil ) Avu cer dururgisthm Umveiaulktikhnik tit Freiburg Br. (Director Prof. Ox. E Rhn) -= (Z. N*curirvfcc. Ifc, IU-SM (kttl). tiM**K**t*ft m 1 April lf\i o> A). f 1. In Ubvttiiutinununx mil Oppcnbnntr wird Imgmit-llt. tUii Foiien ^u> tvurt.ervt- tcr Cellulose lie! Implantation an Ratten emnerragen stud . 'i. gcntultene Claswofte erxeugfe in KuntroMvenuiiu'n keinen krebv 3- Mit swdeodein Benin! rutahiene und rev*, ohne Zusutx hrrgrstelitr Kolu n am rejrnc- licrteHCellujoae warm eheato <.-ncrro*en wir dai Handrlsprodukt. ^n53n3ia<fct< caacerogrtie Wirkung dar Foiien wud mu tier .Silikusv* meugenden Wirkung polymerrr SiUkatc und dat Krebs erzeugeeden Wirkung von Asbmt. vun biiunktio- aelien Mathylolamidee. Aibylemnuaro. Epozydan aerwu* van V-Lust-Vertiiudungt'n vergiichen und daraul braogra. dafi sub funkttaaiwKhtigr Zrllprotrine tuit den linearen MakrranolekuU-n durdi Restvakrazm (Waiaentoff-Binduagen; vernetzro und demit veraadert warden 5. Die hieraadi ru rrwartrade cancerogene Wirkaamkeit vim Pol^argj^-Fober^wud an Ratten fcatgesiellt. X adi implantation von Plattchen aua dem Kurut- ten die vurbor mit Benzol eztrahierten Foiien ebenso Nstuff ..Bakelit" unler die Haul von Ratten be- Kretis (Abb. 2), wie das Ausgang*material und wie obaehtete T u r n e r1 die lukale Entstehung vun SaFr-oiien. die fur dicaen Zwedt am rcgi-neurrtcr Cellu- komen. Aus dicsem Crunde lubeti wir untenudit >ih luec ohne jedm Zuiatz bergostellt wzren (Abb. 3). auch andere Kuiutatuffe eute krebaerseugende Wir Die krabaerzeugende Wirkung kommt also der poly- kung haben. Uber die Ergebmise der 1049 begon- meren Hydrocellulaae selbat zu. nenrn Venuche, die ait tnsgewunt 281 Ratten durdi- Die Ceadiwulste traten zwiacben dem 100. und gefiihrt wurden, soil hier kurz beriditet werden. 600. Tag nach der Implantation auf. War diaaa uftter Ratten unserer Inzuditstamme BD 1 und BO III. die Haut erfolgt, so cotstaad metst ain lirmafnw p6- bei denen aeit 1937 tuemals spontan Sarkome auf- Oerer Krebakaoten, in dmaeo nefaotisdmr Hfibie die getreten sind, erhielten mehrese plenniggrofie Sdieib- Fttttcben lagen (Abb. 1). Die Rattan, daman dia Ptttt- eben handelaiibiidier Folie aus regenenerter Cellulote dien in dia Beudthrthla eingepdaazt waran, zolgtan (HydrocelKiioae) uoter die Haut bzw. in die Bauch- dagegen meist ohireidw UefcMte Sarkome, dia voo hBhie eingepflanzt. Insgcsamt 13 von den linger als alien SteUec aimgiagen. an denen die FUtUben ein- 1 Jahr tiberiebenden 50 Ratten entwickelten lokal mal geiegen baben mnditen (Abb. 2 und S). Dtese Sarkome " (Abb. 1--3 *). aelbat lagan meist bei der Sektioo Irai in der Bauch- Den gieidien Belund hatte vut uns Oppechei- bfihle und arsdueoen audi nacb mehr als 15 Monaten m e r ' erbuben, der ebenfalls nadi Implantation von unverindert. Die cancerogene Wirksamkeit der Po Ceilulose-Foiien an Ratten Sarkome beobaditeta. llen mull danadi stark rein. Zur Autlflewng von Krebs Seine Ergeboisse, die uns aus aufieren Cronden ent sdieutt eine Zeitdauer des direkten Kootaktaa zu ge- vor 2 Jahren bekannt wurden. stimmen mit das un- nugan, die waaeodids kieinar ist als die Latenzzett aereu in alien Punkten iibereui. ^ba znm Auftivten der Cetdrwulste. Die daasit gasidierte kr#Merzeugeade Wirkung der In Futtetungzvenudicn mit zerklcinerter Folie be- Cellulose-Folie kann nidit auf Verunrctniguagcn oder obachteten wir buher each 2 Jahren etnen PsM voo Zusiae bezogen werden. denn wir fsndra Eztrakte. lymphatiadier Leukamie (Lymphosarkom) mit bds- digrAus den Foiien mit siodendrgi Benzol bergostellt artigen Infilttatan io den Lympbknoten, der Leber, wrfren. mdit cauicerogen wirksam. Dagegen arzeug- | der Milz und der Lunge. * Abb. 1--3, s.Talai fci a. ** T\m die hiatolngiadw Dupoat dankca wir dee Har- ran Pruf. H. Ham per I, Marburg, and Dr. W. Altm a a a. Fimburg. ` F. C Tamer, J. mu. Cancer Imt. . gl (IMl}. * Dw Arbeitaa amrdaa durdi diaDautscbaFor- aehu a (sgamaiascbaf t armftglidit. *B. S. Oppeaketmer. T-E-Oppaabaimer u. A. F. Stoat, Tkataact. Ass. Amar. nytraaae I48. 343; Froe. See. aap. IwL MatD7. 33 ------ DUP 1141948 "+fs. % 864 H. DKUCkREY UND D. SCHMAHL Kontrnllversudif. in donen wir 12 Ratten zersto- Bene Giasuiulle in die Baudihiihle unplantierl lialtcn. lieierten kcine Gcsdiwulst Entspredieud drr all- gemetnen expenmentellen Eriahrung ist der chro- nutdic imxlumstiie Reiz allcm attu nidit i-unccriigcn. Die canteruitene Wirkung der Fnlien muB daher auf die SubiUuz der Folie bezogeii werden. -- Die linearcu. inakrumolekularen HauptvaJenzkettcn der Cellulose kind in den Fnlien durdi Nebenvaleoa- krafte zu emeni inizellaren Verband verkniipft, (lessen Ordnungazuitand weduelt und nidit defimyrt ist. In Wasser quetlen die Folien. iadesaen ist eine Luaung in den Kbrperflussigkeiten kaua denkbar. An deu Oherflachen der Foiien Itegen dagegen Biodungs- kriiftc frei. dutch die z. B. Farbstoffe sehr fest ge- bmiden werden kbnnen. Die Tatsadie. dafi Buoreszie- rernle SubsUuueii von den Folieo nidit abgrwasrhen warden konnen. wird sugar als Untertcbeiduiipimerk- mal fur Hydrocvllulose-Folien von Folien andeier Art benutzt*. Daaach liegt der Gedanke nabe, daB audi lineare Zeilpruteine, t^ie in geeigneter Orieutierung nut der geqiiollcnen FoUanobtrfliidic in gemigend engrn Knntakt kiunnasn. von den ebcnialls linearen Makro- molekulen der Kumtjtode z. B. dutch Wasserstoff- Bindungen sehr fest gebunden werden kfinnen. und daB auf diese Weise die krebsige Entartung voo'Zei- len bewirkt wird. Audi eioe Abl&tung euzelner. so init tinea Zellprotein verbundener kunststotf-Mnle- kule aus der Oberfladhe ersdiemt denkbar. Damit wurde gleichzeitig euie Regeneration der aktiven OberBadie verbundan sein. Fur einen sokben Medtanismus spredieo zahlreidic Beobachtungsn aus der letzten Zeit. Earle* (and an Cewebekultureu, die auf Hydrucellulose-Folien ge- zikhtet waren. to vitro tine -jpontine" Canceruie- rung oocmaler Zellen. die duith Retransplantation der Kulturen auf glekhartigeTiere bewieeen wurde. Nadi den Bcfunden von Oppenhruser' und uns bat ten wir es ffir mbgfcdi. daB die boobazhtetc Canccri- SMrang auch hier den Kunststoff-Folien zuzusdirei- ban ist. ___ C. S t a d6 r, Z. angew. Cham. 42. UOH U7). ' (. I Saaford, W. R. Earls. E. Shelton, E. L. Sebilliae, E. M. Ducheaat. C. D. Likely a. M. M. Beck4k. ]. aat. Cancel lot. It. SSI IHfiQj. K J1 g e r. Koilotd-Z tig. 16 [19Sft|. Vortrag Silihem-Tagung MAatler 19. Oktohar 1949. .koiloiddicmiacbe Casuhtspunkte ia der Staubluagrafondiuag* la Jittmdinner; . Die Staubluegeaerkrankunfni . Darmstadt 1980. -- .Staablaagenfonchiiac and Goworbchygienr". neaeuntngeKallt von K. W. fatten, Beedwarfaaiiibinit 1*61, Nr. 10. Em iilinlicher Wirkungsmediauornus ist iur die .Siiikose" crzetigcnden Silikate unzunehinen*. Monomere und amorphe polymere Silikate erzeugen keine Silikose, dagrgen krisullme Polymeiu, und zwar uni so sduieller und starker. )e hbher der Ordnungszustand in den Silikaten 1st V Das Ladungsmuster der Enstallite stunmt nut dem im Eollagen vorhandenen auffallend iiberem. Audi hier wird es aU wabncheinlkh angenommen, daB Zellproteine von den linezren polymeren Silikatmolekiilen an der OberBhche gebunden werden und dafi sich die gebildetes Aggregate ablbseu kbnneu, wobei die aktive Oberflicha wieder regeneriert wird*. Inzwisdien wurde die relativ guts Lbsliehkeit der oberflidilidien Lagen von Quarzpartikeldien nadigewiaaen**. Fur eine Lowing tpricht sdiou der Nachwcis von KmseUiure in dan Kbrperliissigkeiten. Die Quarzteiichen kbnneu von Zalle zu Zelle weitergereidit werden und dine dabei verandcru. ohne ibre Aktivitat zu verlieren (W. C ias e. zit. a. J a g e r *). Die .Silikose" eneugeode Wirkung (timmt pharmakoiogisdi insofern mit der krabaoneuganden Wirkung iiherein, all beida irrevenibel sind und bain Mensdien oft erst Jahrzehnte aadi der Exposition manifest werden und sum Tode f&hren kbnnen. 1m Albert, der ebenfalls im Korper nidit IfisUch ist und trutxdem sowohl boim Monscben' alt atab ex perimenter! am Tier* Lungenkrebt arzeugt, Segt ein weiteres Beispiel fiir die caacerogone Wirlumkeit polymerer Subslansen aus linaaran Makroootekulen vor. Der gleidio Wirkungwnochanianus ist oath neuesten Untenuchungen audi filr viar aadero StoS- klassen wahrsdieulkh geworden, die ama .radiomimctisdie' Wirkung auf Zellen haben und sowohl cytotoxiscb als audi mutagen und cancerogen sind. niimlich Urthyloiawiide, AiAyferWirunw, Epoxyda und die in vivo z i Athyleoiaiaeo bzw. zu Epasyden veranderbaren Sikkttafi-Lott-V*rbindune*n (Tafel 1). Einige derartige Substanzen wurden in Deutsdiland sett lingerer Zeit zur Vorodelung von Teztilien verweadec Sie erzeugen bUibende Var&nderungen an Cellulose- odor Prolainfasern, uod zwar dadur^, dafi * R. ] i g a t, Wtchseiwiikungsa zwwdicn Quan und Orgamssiua Vortrag Bochina 1931 im Dnai in: Beur.ige Silikosafonchg.. H?t 1& Bodiuai 1SS2. E. J. King. Ocx-up. Med. 4. 99 U81Z1. P B Dempater u.P. D. Ritchie, Natun [London] 199. 338 [1932]. H.W. Wed I rr.Dtsch. mod. Wuhr. 99.575 (1943] . *M. Nordaauo u- A.Sorge, Z. Krehaforsdig SI. 198 (19411; W. C. Hueper. .Occupational and eas-iraanwoul caaon", Puhl. Health Rap. 1948. 209. DUP I Ml949 CANCEHOCENfc WIHkl/NC VON K U N ST STO V P F O LI E N ;i;j5 Metliyiolamidr; HOIItC NH 8 \H c;H;OIl Athvienimine: Ljxjxyde. II,C- Cll \./' NH R CTT- CH, N-Lml-VerhmdunKi'U. /CH, CH.CI . R-N< N:H, CH,a * H.C-CII, V' N* A R CH, Cll,Cl _ /CH, ch/; KN( N:h -- ch, & \y/ Tsfel 1. CtBonoMnw Subttanzen (tuuii il r ti d r v "I mc durdi Restvalenzen Ungitseits von deu Fascru gebunden warden odar Vemetzungen herstellcu. Mil dieuen Subetanzeo wurden in \itru such Verundvrungen an Nucleinikuren beobathtet *. Bei Einwirkung auf aids teikode Zellen eneugen sie sichtbare Abnormalitatea an Chrotnoeomen die deocn each Strahknwirkung entsprechen (.radiomimetiMhe Wir ing"). Erne cancerugene Wirkung kooimt vorm-hmlidi den bifunktionellen Moiekiilen zu, alio deo W*-Methyloi-amiden, bte-Epozyden, /nr-Athylemmioen und bu-fChiorathyll-alkyl-aminen'1. Diese Suhstanzen geben in vitro wahrstbeiulidi Radikaia, Jedenfalls ' ilden sic out Lakbtigkeit Vineare Polyiaere. Die cytotoaiiche, mutagene und auifailend itarka conrerogena Wirkung von kubstanaan diner Art wird darauf bazogan. dali die Mooumeren tin Korpcr lineare Poiymere bilden, die *id> dann ahnluh, wie das m vitro nit Celluloae, Protemeo und Nucleinsiiuren beobathtet wurde*, nit tunktionfwicfctigeii Pruteinea uder NucJeopriXrinco der Zelie, die .Du- pUkautcn``-igensehaft beutzen, veroatzen odei der Liinge nach verknupfen und sie so ineversibel verundem nder bloduereu11. Dali im Korper derartige Polyincnsaiiouen taUadilich staltfindcn lcoonen, und zwur audi solchc. die in vitro nur mil kaulysatoren verlauieu. wurde kurzlith am Bei.picl des Acrylamids uezfigt also eiuer CrundxulisUiu (iir widttige kmi.l.\tniU'. Auf uutcerugvne Wirkung wurde Acrvlanud nodi nitht unterxuiiit. Die einfatbste cancemgone Substatu out divsen Reibcn ist das Butailieu-dicpuxyd '* (1). y\ CH, -- CH CH -- CH, \o/ (1) Die Polymeran der aktivsten Substanzen dieser Reihen ztigan zwutiteu dan brutkeobmdungxfibigen Atomen Abstiade von 3,7 bzw. 7,5 A, dia denan rwisthen dan Purin- bzw. Pyrunidin-Kemen m Nucleinxiiuran entspracheo". Das gilt aber nidit streng. vielmehr siud auth Subatanzen out abwetebanden Absiandswcrtan noefa wirkaam. Dagegen find Subxtan/en, drren Potyasare kaine Brudteabinduagsk'aliigkciten haben, nebt aktiv. Danut ist as wahxMiiemlidi, daB nicht nur.das Vorhandensein van fraen Restvalcnzcn, genauet von o-Elaktrooan- odar Pro ton-Doostoran (Or dia gaaanMao pbarmakoiogiscfeec Wirkungan waseotlieb ist, aondern atscb ihre raumIkbe Ordnung, z. B. ibr Inrrnr Abttand vooemander in den Poiymeren. * Hendry und Mitarbb. diakutieran tines soldien WirkungsmechanLunus audk (dr die caaeerogeneu aromatitdian KuhlenwaisentoCa und Amina11. An anderer Stella'* haben wir gexeigt, daB dia Eigansebaltan von aromatiseben Ammen, die ihre cancerogene Wirktamkeit bestimman, m vielen Punkten mit den Eigenstbaften von Farbatnifen ubereinstuooien. die litre -Suh.tantivitat" bedingan, d. h. ihre Fahigkeit, au( lineare Celluknefasem .dirckt" anfzuziehen Sokbe Geaubtspuukte enebeuwn Kir die Pliatmakologie deshalb liedeutsum, weil die wesentlidien Funktimutrager in der Zellr. vor ailem snlchc * D, T. Elmore, J. M. Cut land, D. O. Jot- tip Mt'li- P, W. T a y 1 o r , Bmthein. J. ti, ana lltHM > *. J. Coldaerv. A. <6. u v e I e s s u. \V. C. J Ron, Nature (London) 1(3. 087 II948h U.P. S. Phillip*. ). Pharuwcul. exp.Thrrsprut M. tSlIiSUL J. A.H'amdVy. P L.Ro.eu AL-Wal- pole, Bril ]. Pliamaool. Chemotherapy 8. 201 119511,. J. A- H cnd r y, F. L. Ros*, A. L. W 1 p ole u R F. Homer, Bnt. I. Pharmacol. Chemotherapy 0, U. as: uei}. '* C. Wilke. Nalurwiss. 96. M2 11861]. 11 J. A. Hendry u. MUarbb., I. c. >`. 14 J. K. D i x o n. C, L. M. C h r i s t o p h e r u. D. L Ssllcv. Paper Trade J. IV. 455 (1M81. J. A. He ud r y u. M.urhh . l.c. >i. >* II. Druckray. D. Sehaihl u. P. Omni, here. Nalurwiss. 16 {1852], LDrodc. ** Th. VikkarstsH, .The pliyucal cbemutry of dyeing* Oliver Ir Boyd. London 1950. DUP 1141950 4 Him CAN C E ROC E N K WIRKVNO VON k l NbTSTOKK-FOU t S mil .DupiikuntiMi"*Ecruvduift. liiwjrt Makromok" (lime l.i-uebe jidi imr *eultlxii. kuum- eber VuW` ilurtiin *\ . jdwmisch sun den entkpreihcnden Fulien unteredirv AK \'t>funsM*(/unv: iur Ijr bimJtuiu .iii limMrc den. mul! es lur inoxhth *e!ulu.*n werden, del) such M.ikroimiltknlr (|<H Za'Hc imili <U* Virh.unlt'i%riii ' die merbamsdie VerieDiiiii; vun Zelleu duni die urn KpiWuUni/kreiJunt m iUn kvinswtfti*n ancrnom* sdiurte kaute Jer Kulien lct direr c-uiK-rm*enen Wir- itwii uti(lei). Wir rim* PnK kmii' erne Rolle spirit und s-iellrwht dime etninlet. tUt Imrn.uii uku\ mmh muBtc. auf raiKfn'^rtif Wit- 1 Kur sub altcin kaiui der chruniuhe iDedianiicfee Rnz kune umtTMidit. uih! /.vnr i'C`uproliCt4m*Ktii<'n (11) iiidestrii kemeu Krci* erzcuitrn. sk dec negative H; M ||, II, O U? Aiuium: uiiseter KunlruUsenudie. in dense nerstoBene (doissnlle unpLuiticrt wurdc. enimit angt. Die kiibstuulfelle Wirkunf;. der Fulien mud debar das H O 11, H, H, I! 11, WeMntluhe sem. bu mug der Mecbanumus dieser Slixiktur drt t 1 caneenutenen Wirkuug son linesren PoVyawrc shn- luh livumi v ie drr b der Inickturn oil den Rom* 9 Ratten wtmien te 5 FidieiiktiKiihrii son Plenum- Sarkimi-Virun. die ebenUlb erne Verietzunx von Zel- "S mbltr iii die Baudihidile iiuplaiitiert. Nath &<0 Taiirn ten vsinuusetzt Die eulfewnrienen Problems stud leliteu imcb li Tiere. Virr dassm haheii lusher mul , dein Es|H`riinenr /ugauittkh. tiple und M'hr hAsartixe Sarkonie enlwKi.elt. die iiber Neill den bulier sswlicncndcn Befuaden no8 gc- ilrn iwiuen Baosliruiire vertitit seareii (Abb. I *). Die lordeit werden. dell die Verwenduaf pnlymerer Wiikunn entsprniil snllkonimen dor sun t a-llulose- 1 Kuiutklidfe als pleetmbe Meskcn iu drr UurunOe fulien umt xbeim nt,ii starker /u sem ah tliua- . dire tiiundliibe Pruliuii! in Daiieriersudirii oie Tier H c n d r y bcriditet in eutviii Naditrag inner | soruuvset/t. Dir caneermicn xelundenra KuuMMnie ' d Irtxten Arbeit. dafi das deni i-Capiolactam Pols* | durlen tut diesen 7.wi. imbt 'rskendet erdec. - v mcrisat srbr nahe sensandte (laprus baths Icu-iinui (III) stark cancCTuitrii sei. Onentiercmle Versuche H, H, O VI, cyc\<-yc\r-yc\s H._ li, H, ' 11, ~ Caproyl-athylrainiiu uin r if nut einigeu Kunsttcxtilien. wic Oriun, Nylon* und Prrlungewebe srrliefen biiher necutiv, abwoht die Beuluditunmcit melir ah 10 Monate betruxt Du Naelilra|i li. il. k u r r..- Kilr/(idt teiHm O p p * hi'imer u. Mitsrbli 11 weiiert* Kefunde mu kunktetulfim an Ratten und Mauken mil. Geimme Ceilnpbeniln a, reuuien in etws 90% drr Kalle SarLmnr. varber eut Alb>Iki) estreliirni' KiIhk* ko|(*r in 49N Drr AlkubelrkUtkt war ibyecen wirkunicslia kontmllvrmidie. et denes CU>* pbtttben nder Watle nnpUntierr warm, ersaiwn krtnni kn*tis. Dim' CrildoTiiM1 desitm Hii sclllii: nut dm uiucn VmvkihlnndfilnM' waxen etwa rhensn wirksam ww Cello* pfcanfilnie, Pidyntlisieniulirn daergen deutlicb arhwidier 1)9%). ww es eacb den lurr rntsndieUcn VreUellunxm uher (be Redeulum brikiienbindunplihixeT Cmppen 1Or dir Wiriuainknt erwanet wrrden niudlr " H. Steudinger. -MsknxnsilckuUre Ornate tied Bxdojw*. Wept, Bose) 11UT. `Dorrr. Bleyert u. Schmidt, Z. Krafas* touch*. M. 256 [1912] Abb. 4. s.Tairt S.9&ls. '* Brurfl MmiciIuhx und B. S. O p p r n h e t m r r. t. T O p p e n h r i in r r u. A. P. Stout, Pros' Sue. exp. Bnl. Med. TV, 366 (laU). a. } DUP 1M1951 TRANSLATION from: German W3:vr J. a foulger, m. d. CANCEROGLNIC ACTION OF PLASTIC FILMS (The research was made possible by the Deutsche Forschungsgemelnachaft) By Hermann Druckrey and Dietrich SchmHhl From the University Surgical Clinic of Froiburg i. Br. (Director: Prof^Dr. E. Rehn) y (Nnturforachung 7b, (1953^_Rceivod on April 195?) 1. In agreement with Orpenheimer it is found that regenerated cellulose films ore cancerogenic upon implnntaticn in rats. ^ 2. Pulverized glass wool did not produce cancer in control tests. 3. Pure, regenerated cellulose films made without addition and extracted with boiling benzene were Just ns cancerogenic as the commercial product. 4* ?he cancerogenic action of the films which was observed was compared with the rsllicosis".producing action of polymeric silicates and the cancer-producing action of asbestos, of bi-functional methylol amides, ethylene imines, epoxides and N-mustard gas compounds and attributed to the fact that cell proteins of functional importance are crosslaced with these linear macroraoleCuloa by residual valences (hydrogen bonds) and thus changed. 5. The cancerogenerlc activity of nolyamide films which was accordingly to be expected, was actually noted on rats. Upon implantation of small plates of the plastic "bakelite" under the skin of rats. Turner CF. C. Turner: J. net. Cancer Inst^. 2, 8l, (19i*l)J. observed the local pro duction of sarcomas. For this reason, we investigated whethe othz* plastics also have cancerogenic activity. Below, the results of the experiments commenced in 1949 carried out on a UVTIir S MIBCMAMTI' TliNIUTlOM BUBBAO Cat T. 1--rti CmMiMmAmI w. Bm*. ~ to, ifot Fmokb Dior 449&-29M U Bkusway. Niv You < N. Y. DUP 1141952 TRANSLATION from'. 'TT 2 total of 28l jpats will be briefly reported on. pats of our inbred strains BD I nnd '*D III In which, since 1937* sarcomas had never occurred spontaneously, were given several small plates of the size of a penny of commer cial, regenerated cellulose (hydrocellulose) films, imnlanted under the skin or in the abdominal cavity. A total of 13 of the 50 rots surviving the age of one year developed local sarcomas (Figs. 1 to 3) (we wish to express our thanks to Professor H. Hamperl of Marburg and Dr. A. Altmann of Freiburg for the diatological diagnoses) The sane finding had previously been mode by Oppenhelmer Qi. S. oppenhein.er and A. P. Stout, Transactions Ass. Amer. Physicians 1948 343* Proc. Soc. r.xp. Biol. Ved. 67, 33 (1948)/* sho also observed sarcomas upon the implanta tion of cellulose films in rata. His results, which due to reasons over which we have no control, became known to us only two years ago, fully coincide with our results in all noints. '*he cancerogenic action of cellulose films which has thus been proven cannot be attributed to contaminationso:* ad* ditions for we found, that extracts which were prepared from the films with boiling benzene were not cancerogenlcally active. On the other hand, the films previously extracted with benzene produced cancer (Fig. 2) in the same manner as lCwilfY.rlwimiter a MIICMAMTI' (7 Wtsfeamn) sianow 9UBIA0 Wa. ImW l*M Simms DtOST 409)04931 11 'IT, NSW YOB < H. Y. DUP 1141953 TRANSLATION from: the atarting_jnaterial and as film# which were produced for th.a purpose~from regenerated cellulose without any addition (Fig. 3). The cancerogenic action therefore is due to the polymeric hydrocellulose Itself. The tumors occurred betweei the 190th and_600th day after the implantation. If the implantation was made under the ski"), there genern Uy occurred a single large cancerous node in the necrotic cavity of which the s^all plates were located (Fig. 1). 'The T^ats that received the implantation of the small plntes in the abdominal cavity, on the other hand, generally showed numerous smalTer sarcomas which started from all places where the small plates might at some time hove lain (Firs. 2 and 3). The latter themselves lay mostly free in the abdominal cavity upon dissection and did not appear to Pave undergone any^hange even after more than 15 months. The cancerogenic activity of the films must therefore be strong. For the producing of cancer there appears to suffice a period of direct contact which is substantially smaller than the latent period until the occurrence of the tumors. in diet teats with comminuted film we have obeerved up tojnow after two years one case of lymphatic leukemic (lymphosarcoma) with malignant infiltrates in the lymph nodes, the liver, the spleen and the lung. Cohtrol teats in which we implanted crushed glass wool in the abdominal cavities of twelve rncs did not UVTIll1 * MStCMANTI- TRANSLATION IV1IAO CiriV.ancfet irwWMlmilmil hi ISM rsOM Dior *3930-29)1 a laQAOWAT. NSW YOU 4. N. Y. DUP 1141954 TRANSLATION from: ~T7 I~ *" :i raault In any tumor. Corresponding to general experimental experience, chronic mechanical irritation alone is there fore not cancerogenlc. The cancerogenlc action of the films must therefore be due to tho substance of which the film is made. ^ -- The linear, macromolocular main valoncy chains of the cellulose are bound in the films by secondary valency forces into a micell association the order of which changes and is not defined. The films swell in water but solution in the body liquids is scarcely feasible. On the surfaces of che fixms on the other hand there are free binding forces by whicr:, for instance, stains can be very firmly bound, xhe fact that fluorescent substances cannot oe washed off fre m the films is used even to distinguish hydrocellulose films from films_pf other kinds (C. Sandor, .1. angew. Chem. l2, 110b, 19371. Accordingly, the conclusion suggests itself that also i;neojvcell proteins which cone into sufficiently ciose contact in suitable orientation ..ith the swollen film-aur- face, can be very firmly bound by the likewise linear mncromolecules of the plastic, for instance by hydrogen bonds, and that injtnis manner the cancerous degeneration of the cells is brought about, ^ven c separation of Individual plastic molecules bound in this manner to a ceil protein from the surface appears feasible. A regeneration of the active uVtiii * miichamts' thkiutiom sesiso OH V. Umm tmrtm) V M li h 1901 MOMS OiGST 4-29XX2931 BSOABWAT. Not YflSK 4. N. Y. DUP 1141955 TRANSLATION from: -5- surfoce would at the same tine be connected with thia. Numerous recent observations speak in favor of tuch a mechanism. Earle Qc. K. Sanford, W. R. Earle, E. Shelton, E. L. Schilling, *. M. Duchesne, 0. D. Likely and M. V. Becker, J. nat. Cancer ^nst. 1_1, 351, (1950^) found in vitro in tissue cultures which were grown on hycrocelluloae films, a "spontaneous" canceration of normal cells, which was proven by re-transplantation of the cultures to similar animals. In accordance with the findings of Oppenhelmer (loc. clt.) and ourselves, we believe it possible that the canceration observed is also in this case to be ascribed to the plastic filmsw A simllcr mechanism of action must be assumed for the silicates producing silicosis j(3. JUger, ICollois-Z., 119, 165 (1950^. Paper read before' the Silicose Convention in Munster on October 19, 19L9 entitled "Colloidal Chemical Considerations in Pneumoconiosis" contained in JBtten-Glrtnef: "Die Staublungenerkrankungen", Darmstadt 1950 - "Staublungen fbrschung und Gewerbehygiene" edited by K. JBtten, Bundes r- beltablatt 1951. No. 10). Monomeric and amorphous polymeric Liliustes do not produce silicosis but crystalline polymers do, doing this all the moru rapidly and strongly the higher the order in the silicates (ibid). The charge pattern of the crystallite coincides strikingly with that present in collagen. Also in this case it is ossumed probable that uvntr mtciiXTr tkanslatiom sosiao V. aMW (Tm i into Im) 19M Star 44930-2931 11 ISQADVAT. NSW YOU 4. K. Y. DUP 1141956 TRANSLATION from: -7- meric substances consisting of linear macnomolecules. The sape mechanism of action has also become probable in accordance with very recent investigations for four other claasea of aubatancea having a'Vadiomiraeiic" action on cella and are cytotoxic aa well aa mutagenic and cancerogenic, namely methylol amidea-, ethylene iminea, epoxides and the nitrogen-mustard gaa compounds (Table 1) which change in_ vivo to ethylene iminea or epoxides.| Some ofthese aubatancea have been uaed for a long time in Germany for the processing of textiles. They bring about permanent changes of cellulose or protein fibers] in the manner that they are bound by residual valences alongside the fibers or produce cross-lacings. Changes of nucleic acids werejlso observed in vitro withtfaaes substance^ f(D. T. felmore, J. M. Gullanc, L. 0. Jordan end H. .V. Taylor, Blochem. J. U2 , 308 (191*8^. Upon anting on dividing| cella, they produco_visible abnormalities on chromosones [(B. J. Ooldacre, A. Loveless and A. C. J. Ross, Nature (London) 667 (191*9)] which correspond to the abnormalities noted after irradiation ("radioraimetic action"). A cancerogenic activity devolves predominantly on the bifunctional molecules, l.e. the bis-methylol amides, bis- epoxides, bis-ethylene iminea and bis-chlorothyl-alkyl- amlnea/(F. S. Phillips, J. Phormaeol. exp. Therapeut 99, 281 (1950); J. A. bendry, t. L. Hose and A. L. Walpole, Brit. J.| Pharmacol. Chemotherapy 6, 201 (1951)7; R. F. Homer._________ uvrui' * MSEC W AMT S * TliM *t ATI ON IV1I1D Ti rwoMS Dion *393*3931 hi lfOt 11 Somovat, nsw Yobs < N. Y. DUP 1141957 TRANSLATION from: 8 Brit. J. Pharmacol. Chemotherapy 6, 235, 357 (1951). These auostancea in vitro probably give radicals; in any event, they readily form linear polymers. The cytotoxic, mutagenic and strikingly strong cancerogenic activity of substances of this type is attributed to the fact that the monomers form linear poly mers in the body which In the same manner as ess observed in vitro with cellulose,proteins and nucleic acids (D. T. hlmore, et al, loe. cit.), thereupon cross-lace with functionally Important proteins or nucleo-proteins of the cells whichjiave the property of "duplicating", or connect onto them in length and thus change or block them irreversibly^(F. S. Phillips, J. Pharmacol, exp. Therapeut 99. 28l (1950, jJ* A. Hendry, P. L. Rose and A. L. Walpole, Brit. J. Pharmacol. Chemotherapy 6, 201 (195l)'< A. Hendry F. L. Rose, A. L. Walpole and R. F. Homer, Brit. J. Pharmaco.. Chemotherapy 6, 225, 257 (195ljj The fact that such polymerizations can actually take place in the body, as also such which take^place In vitro only with catalysts, was recently shown on the example of acrylamide, (0. Wilke, Haturwiaa J8, 532, (1951;), i.e. a basic substance for important plastics. Acrylamide has not yet been examined as to its possible cancerogenic action. The simplest eancero- genic substance from ttils series is butadiene-d-eroxide (J. A. Hendry and co-workerloc. cit.) uvrur a wikcramti' tiamilatiom bobbaq Get V. taW (Twtata tata taw) We. Inert i " ta 1904 PMOKB Dtasr 9*MM1 11 tao-uxtAt. Nit yobs 4, R Y. DUP 1141958 -rjTftS3mrnm!*m - ...toiEi; i TRANSLATION from: -9- . y\ ^ CH? = CH CH = CH? </ *0 The polymers of the most active substances of O these series^ahow intervals of 3.7 snd 7.5 A between the atoms capable of forming bridge bonds, which intervals correspond to those between the purine and pyrimidine nuclei . respectively Jn nucleic acids. (J. K. Dixon, C. L. V. Christopher and D. L. Salley, Paper Trade J. 127, 455 (1948) J. A. Hendrv and co-workers, loc. cit.). However, this is nfct strictly the jase, but rather,, substances having different interval values are also active. On the other hand, substances the polymers of which do not have any ir ability to form bridge bonds are not active. Thus it is probnblo that not only the presence of free residual valence: more precisely of ^ electron or proton donors, is essential for the said pharmacological actions, but also their spatial arrangement, for example their linear distance from one another in the^polymers is also essential. Hendry and co-workers discuss such mechanism of action alao for the case of the cancerogenlc aromatic hydrocarbons and amines (loc. cit.) at another place (H. Druekroy, D. Schnlhl and F. Danneberg, Naturwias, 1952. in _0 press) we have shown that the properties of a-omatlc amines which determine their cancerogenlc activity is identical in many points with the properties of dyestuffs which deterainb uvrur a miechamts' teamsiatiom iviiao C*T.a*te ; Dior 4493049SI 11 IBOAWAX. NSW You 4. N. Y. D(jp 1 141959 TRANSLATION from: -10 their "subs_tanti vity", i.e. their ability to be absorbed "directly" pn linear cellulose fibers (Tfa. Vlkkerstaff, "The Physical Chemistry of Dyeing" Oliver Boyd, London, 1950). Such considerations appear of inportance for pharma cology for the reason that the essential functional carriers in the cells, particularly those having "cuplicating" properties, are in all probability linear raacromoleculea (H. Stoudinger, "Mnkroraolekulnre Chemie und Biologie", .Vepf, Basel, 1947). 'As prerequisite for the linkage at linear macromoloculars of the cells, there must be assumed the presence of residual ^alency forces in the plastics. Vie therefore examined a polyamide film which, in accordance with this, would have to be active, as to its cancerogenic action, selecting for this purpose ^-Caprolactam films (III), In the abdominal cavities of each of 9 rats there were implanted five pieces of film of the size of a penny. After^360 days, 6 animals were still living. 3 of them had by that time developed multiple, very malignant sarcomas which were spread over the entire abdomen (Fig. 4). The action corresponds fully to that of cellulose films and even anpears to be stronger than the latter. Hendry (loc. clt.) reports in a supplement to hit latest work that caproethylene-imlne (IV) which is very cloaely related to the ^-caprolactam polymer is strongly UVYIII' m HIICK1NTI' TllM tlATIQM SVISAO Cmt V. Brack* (Trarfara irate tera) Vm. Ik tfW Pucwa Dion 4293S-2931 11 Baourn AS, Ms* You < N. Y. DUP 1H1960 TRANSLATION from: 11- cancerogenic. P-ellminary investigations with a few plastic textiles such as orlon, nylon, and perlon .have up to now proven negative^although the period of observation was more than 16 monthsInasmuch as these fabrics diffored only In shape but scarcely chemically from the corresponding films, it must be deemed possible that also the mechanical injuring of cells by the sharp edges of the films plays a part in their cancerogenic action and possibly introduces same, in itself, the chronic mechanical irritation can, however, not produce cancer,js again showed by the negative results of our control experiments in which ground glass wool was implanted. The.action of the substance of the films must, ,'Xm. therefore, be the essential factor. Thus, the mechanism of this cancerogen action of linear polymers must be similar to that obtalnod in the case of infection with Rous's sarcomi virus which also_presuppoaea injury of the cells (Doerr, Sleyert and Schmidt, Krebsforschg, 6, 256, (1932). The problems rsised are subject to experimental answer. In accordance with the presently available find ings it is necesfnry that the use of polymeric plastics as plastic compounds^in surgery be preceded by thorough testing by means of long duration tests on animals. The plastics found to be cancerogenic must not be used for this purpose. Methylol amides flOH2C NH R NH CH20H ________________ =-______________________ ___________ PUP >141961 UVTItl' * KlftCMANTI* T11NIIATION IUUAD Cal V. Iwrti (T-ailirta Smtim In) *. In. hL tfO* fmms Oicar 9JO-2931 a fotavAT. Nit Yeas < N. Y. j TRANSLATION from: -12- Ethyl eno laina: = 1 NR Epoxidea: R CH - CH2 V N-Muatard Caa compound!: HsC - ,CHp \ /. N' / R CH2 CH2C1 ^CH2 CHsCl < ch2 ch2ci .ch2 CH2C1 N CH - CH2 \o/ Table 1 - Cancerogenic Subatancea II H i H2 }~2 0 . . li "2 'c'%/H-'c/vcy'V<V (According to Hendry, loc .Cl' u H 0 h2 h2 h2 h h2 (III) Fig. 1*.: Structure of the -Caprolactan-Polynera H2 H2 0. H2 H3 II2 h2 h2 Caprol-ethylhenimine (IV) DUP 1141962 Ucm V. Y--rltiir * MI1CITMmAImMTUI'mmTfteiNwlUlTIOM IO1M0 im Dior JO-3931 tl aeoMWAT. Hie You 4, N. Y. TRANSLATION from: 13- Fig. 1: Single sarcoma after subcutaneous implantation of hydrocellulose^f11m. Arrow shows position of the small disks (rat 2144 2) Fig. 2: Multiple sarcomas (arrows) upon abdominal implanta tion of hydrocellulose film which had been previously extracted with boiling benzene (ret 19?4 % ). -ig. 3: Multiple sarcomas (arrows) upon abdominal implanta tion of pure hydrocellulose film without additions (rat B 346 2 ). 1 Fig. 4: Extensive sarcomatosia of the abdominal cavity of a rat (2128 ?) aftor abdominal implantation of -caprolactam film. tiVYIkl' * MStCHAMTI* TEAMSLATION SUEIAO Oat . Seed*= (TnmUrnigm, 1909 Saw) Wa. Eirarti taOKS Dtas* 11 Ssoasvat. NSW YCBE 4. N. Y. TRANSLATION from: SUPPLY'HIT TO THE PROOF: Recently, Oppenheimer and co-workers* reported further findings with plastics on rats and mice. Genuine cellonhane films produced sarcomas in about of the cases while films previously extracted with alcohols pro duced sarcomas in as many as of the case*. The alcohol extract, however, was without activity* Control tests in which small glass plates or cotton was implanted did not produce cancer^ These results coincide fully with ours. Vinyl chloride films had about the same activity as cello phane films; polyethylene films on the other hand were of noticeably weaker action (13/0, as was to be expected on basis of the theories developed herein on the importance of groups capable of forming bridge bonds, on the activity. + Written communication and B. S. Orpanhelmer, b, T. Onpenheimer and A, f. stout roc. Eoc. exp. Biol, and Ved., 79, 366, 1952. __________ -______________________________________PUP H 41964 HTTItr MI1CHAHTI* TtiMIUTlOM IOIUO taora digit V293M931 im u lu4ff*AT, Kir You < N. Y.