130 Abstracts/Lung Cancer 10 (1993) I23-IJO

Rata cmcogetm point rtwtatiott. primarily activating tbe K-ms gew,basbeonrqmrtediaeppmtimetelyonethirdofkmgedw- carcinomas. Tkis identities e subset of early etege hunore clinically essacieted with smnking and ae aggmesive cliical course. Bsuuee of theset%dings,tbisetudywslmde&~to~etheoocurlence ofnspointmutrtionsinbmnchidorlvw~c.Thisuncommon form of lung adeoawcinome is usually indolent but can somctimss pIwalt es P repidly growing, mldtifocpl tumor. Twsaty humr samplas obteined et thoneotomy were exemined for Has, K-me, and N-ms oncogene mutatioael ectivatkm involving codons 12, 13, or 61. This WLS rerformed bv an olieonuclmtide h~bridiion techiaue followinn

10s point muEIticm involving codon 12 was &m&l in hvo humrs, but not io the adjacat hist&gicrdly beaign lung tiasae. These mutations wrecontinned by direct sequencing of these polymaase cbainreactial pmducts. Both patkIts wem smokers, had aage 1 tumors, and rsrmin di-free at 27 md 40 months postopemtively. No H-res or N-res point mutetions were found. llwse findings suggest tbet ms ectivetion is en infrequent event in broncbioloelveolar carcinoma. We qeadete that me activation is note common trpllsformntionel eveat in this form of lung aden~inOme.

Human small ceil lung eureer expresses the ectamer DNA-biidiqg and nervom systmnqxlfic tramcriptlon factor N-Ott 3 (brain-Z) Schreiber E, Himmlmann A, Malipiero IJ, Tobler A. St&l R. Fontana A. Section of Clinical Immunology, Dqatiment of Internal Medicine, University lfappital, Holdeliwg 4, CH-g#4Zwich. Cancer Res 1992;52:6121-4.

Small cell lung cancer (SCLC) cells express several cbpnmtistics of wunmal cells, including syntbosis of Imumpcptidea andexpressionof~rsspeaivsrrcsptoFJ.hPtlMisbmet~mPin~ of the neuronal pbeaotype of SCLC may depnd on expression of gene tmnscription factors inherent to the c8ntml nervous system. The present shady shows the nervous system- specific transwiptim~ factor N-Ott 3 (brain-2) to be expressed in all 13 SCLC cell lines investigated. Furthermore, N-at 3 (brain-2) was also found in SCLCderived skin metastasis. In contrast, in extracts and RNA of nowSCLC cell lines end non-SCLC tumor tissues, such as lung squamous, large cell, and edenowrcinome, expression of N-Ckt 3 @rein-2) wes not detecteble. These dete support the cwcspt thet SCLC cells derive from the neumectodermal ccl1 lineage since expression of N-Ott 3 @ain-2) protein is highly ebundant et the neural tube stege end in the edult restricted to the nelwoec~ cell lineage.

Orthotopic reconstitution of humansmall+ell luq carcinoma after intravenous transplantation in SClD mice Kuo T-H, Kubota T, Watanabe M. Furukawa T, Kase S, Tanino H et al. Depanment of Sw;prry, School of Medicine, Keio Uniwrsity, 35 Shinanomachi,Shinjuku-kr, Tohy160. AnticancerRee 1992;12:1407- 10.

Wehave constructed an orthotopically reconstituted model of human smakell Itmgcarcinoma(SCLC) by intravenous transplantation in severe combined immunodeficient (SCID) mice. Two human SCLC xenograt?s, Hd9 and Lu-130, were disaggregated and injected through the tail vein of SCID mice. Human SCLCs were orthotopically reconstituted with multi-focal lung tumor growth in all SCID mice after intravenous injectioo of 5 X 106 tumor cells per mouse. The heart and liver were also seeded with actively growing SCLC. This ortbotopic reconstitution model ofhuman SCLC in SClD mice should be useful for further studies on the biological tiavior and treatment of human SCLC.

A new patient-like met&& model of human small-cell lung cancer constructed mthot0pically with intact tissue via tho~temy in nude mice Weng X, Fu X, Kubota T, HotTman RM. AntiCancer, Inc. 5325 Metm Street, San Diego. CA 92110. Anticancer Res 1992;12:1403- 6.

A new nude-mouse metastkzing on&topic transplant model of human smakell carcinoma of the lung is described. Histologically

intact II- emell-coll llmg honors were b-Msplented to the Icf? lung of nude mice vie. tbomcotomy pmcedum we beve developed. The tmespleaed ttmmrs grew exteaeively locally and lmtwasized to the opposite lung, lymph nodea and other cliiully-relevant sites. The results described indicate. the model developed could have clinical ~lev~~contnstswithmodelsofsmpll~urcinompmDshucted withiajectioasofcdl~ioaswhichnsyltin~or~o.

A patient-Iii metas- mo&l of Inmm hmg ~Qwarcinolru coasbudcd via thoramtomy in ??tde mice Wang X. Fu X, Hoftimn RM. Antitim, Inc. 5325Uetro Street, San Diego, CA 92110. Anticmcsr Rm 1992; 12: 1399-1401.

human A549 adeaoam’ moma lung tumors wem twsplanted to the left lung of nude mice. via thohoncotomy pmcedum we have developed. The tnlnsp1allted hlmors grew extezwively locally and llwaasized to the opposite lung, lymph nodes and other clinically-relevant sites. The results described indicate tbe model develolxd add bwe clinical relevance and contrast with models of the A549 lung adeuocMcinomr. constructed otthotopiully with iajcctions of cell swpasimw which result in low l&astatic pot&al.

An mti-mucin lmmmwtoxin BrE34cin A-chain is potently and seleetirely toxic to human small-cell lung cancer Derbyshire EJ, Wawnyncrnk RI. Drug Targming Ldoratory, Seciion of Immunology, Institute of Canm Research. Sutton Sk42 5NG. lnt J Cancer 1992;52:624-30.

Mo~oclo~~ntibodies(MAbs)~~to~~epithelinl mucin or defined carbohydrate struchwes present on mu& moleades were screened for their ability to form cytotoxic agents with rich A- chain active against bumae small-cell lung cancer (SCLC) in an indirect assay of immunotoxin cytotoxicity. Anti-X haptea and anti-Y haptea antibodies binding to P high proportion of SCLC cells mediated only weak to moderate effects on ‘H-leucine incorpontim~ in combiiion with the screening agent. sheep anti-mouse. IgG F’(ab)-ticin A-&in. In contrast. themouseMAhBrE-3, recognizingthepolypeptidecoreof~e MUCl mucin gene product, exerted potent and selective cytotoxic effects in the assay. An immunotoxh made by the direct attachment of rich A-chain to BrE-3 was selectively toxic to SCLC cell lines in tissue culture. The cytotoxic activity of BrEJ-ricin A-&in was enhanced 1 OO-fold in the presence of monensin but not by lysosomotropic amines or calcium antagonists. Our findings suggest tbnt anti-mucin immtmotoxins may have e therepeutic role to play in the treatment of SCLC.

High slrpaptibillty to lung cancw anelyzedintmnsofcembined gewtypcsofP450UlPndmu_dsss~uhtbione~-g~ Hey&i S-l, Wetenebe I, Kewajiri K. Deportmeol of Eiochemisfy. Saitama Cancer Center Rumrda Inrr., Ina-machi. Saitama 362. Jpn J Cancer Res 1992;83:866-70.

Lung cancer is closely essocieted with ciger&te smoking. Aromatic hydnxa&ms in smoke, includiig beaa@]pyrene, first require metlbolic ectivetioe by Fluse I enzymea, cytocbrome P450, to their ultimate forms, and these activated forms a~ thee subjected to detoxificatiatby PbeseIIauymes, eapeziellyglutathioeeS-husfemses. Thus, geneticelly de8e&& susceptibility to lung cancer mey depend on the rm%bolic belenco betweca Phase I aed Phase II enzymes. la this study. we identified individuals genetically at high risk of lung cancer in terms of polymorpbislns of the P450IAl gene and GSTl gene. The relative risk of individuls with e combioetion of the genotypes of both abomozygo~nrellleleoftheP450IAl geueandtbenulledGST1 gene wee remerkebly high et 5.8 for lung -reed 9.1 for squmou.s cell carcinoma compered with other combiitioes of genotypes.

TheFelstio~pofpUimmunostPi~tosuniv~line~reiwmsd the lung McLzwea R. Kwu 1. Dunnill M, Harris A, Lane D, Getter KC. Nu@ieki