Abstracts/Lung Cancer 13 (1995) U-104

departments represent wer 90% ofall microscopicall) vcntied cars of bronchopulmonaly cancer in Slovenia The &en& rose front 370 m 1970 to 782 in 1992. with male ~rcvalcnce (85%) Passive detectmn was prclcrentially used as tua~s tluoroscopy has been gradually abandoned atIer 1972 Bronchoscopy was ah&s the main d#agno& method (92.l%in 1970 and 90 7in 1992). iollowed bvwthoraac fine neddle aspiration bmpsy (3 8% and 4.5%). Gther methods (sputum cy3ology. med~astmoscopy. thoracorapy. thorawtomy) accounted for 4 1 and 4 8% respatwely There is a slight predominance of central type (53 7 vs 46 3% m 1992) Planecellular type was predominating (68.9% I” 1970. 39 8% I” 1992). followed by sma,,-ce,, (IO I and 19.2%).adeno-(Band 16 5%),andlargesell(7and 136%)carcmomas In 1992 surgery was the therapy of choice m 26,3%, chemotherapy in IS% and radwtherapy m 22.5% of newly detected cases.

Lung cancer. The overlooked women’s health priority Sauna L. School of Nurstng, Oniwrsrry o/Califimio, 10833 Le Conre Avenue. LosAngeles. CA 90024-6918 Cancer Pncl 1995;3: 13-8.

Lung cancer is a serious women’s health issw. The disparity between male and female deaths fmm lung cancer is narrowing. and the number of wmen with the disarm is increasing Although health of women IS substantially tie&d by tobacco use. many bwks on women’s health and related progmms da not pmvide information about lung cancer and smoking. Historical dcIinitionsofwomen’s health have limited the awareness of the nsks of smoking and lung cancer as priority concerns for women. The cxcbuion ot smck~ng and lung cancer m the currem literature on women’s health is reviewed. A IO-year rewew of nursmg research in lung cancer prevention and care emphasizes the paucity of work on smoking preventmn and cessation Cancer prevention and detection reman high priorities in nursing care organizations: however. tobacco control pohcies are almost nonexistent The healthcare professional’s role in tobacco ccmtrol and health p&q, wtth special attcnlion to the cl&t on women. is critical.

Social and environmental factors in lung cancer mortality in post-w.r Poland Brown HS, Gable R. Klrschner H. Clr Technol Env,ronmenr Development. Clark “n,ve,s,ly. PJOhbinSrreel, Wwcesrq MA 0,610 Environ Health Penpect 1995.103.64-70

Poland and other Eastern European ccwttries have undergone heavy mdustrial dcvclopment wth marked increases in air pollution and occupational exposure I” the nearly 50 years smce World War II -llxse countries have also experienced substantial mcrwses in chronic disease mow&y m the past three decades Whde it 1s tempting to assume a direct assoaatmn between these phenomena, more detailed analyws arecalled for Polandoffersa potenttally nchopponunity forcompanng geographical patterns ofdisease incidence and of mdustrial change. In this paper we 1) elucidate the prospects for auributing lung cancer mortality to indwtrial emmwms in Poland uring an ecological approach based on the hitherto unaddressed geographic differences, and accmntmg for regional diiTerences in ctgarette consumption: 2) propose explanatory hypotheses for the observed geographic heterogeneity of lung cancer: 3) begin systematx testmg ofthe widely accepted but not well-scmtmmd nomn that pllutmn in Poland is a major wnttibutor to decliumg hfeexpectanq. Regtons with the highest fractwn of cancer that cannot be explained by smoking appear to be highly urbanized, have high populauon exposure to ocsupat~onal carcinogens, experience the highest rates of alwholtsm and crime, and are associated with the post- World War II population resettlement. Although the analysts does not lule out pollution as a rigntticant mntributor to lung caucer mortality. II indlcata that other Iactors such asaxupatioual exposures andvarious soad factors are of at least comparable mportance We conclude that the observed trends in life expectancy III Poland should not be attributed pnmanly to pollution without careful attention to other conttibutmg causes and that social factors. such as Ihe major population resetllement. may have produced living conditwns adverse to good public health. We argue that research on pollution and public health should treat these topzs in a broadcontea mcludmg both technological and soctal change

Occupational assoctitions with lung cancer in two Ontario cities Fmkelstein MM. Health and Sq+ Sfudies Unrt, Onrano &f~nrsrry O/ Lobow 400 UmversrtyAwnue, Tomnlo, On!. M7A IT7. Am J lnd Med 1995,27:127-36

A death certificate kased case-control study of lung cancer in two

Ontario cities was perfomted to estimate the risk of lung cancer attributable to occupation in Ontario. and to estimate the pmponion of occupational lung camxrs receiving campenstttion from the Workers’ Compensalion Board. Dccupatiott and industry were identified fmm the death aticate. A priori OauptionJ for analysis were those whose members had received compensation for occupational cancer from the Gtttatio Workers’ Compensation Board. Population attributable risks were computed using the relative risks observed in this study and employtuent data from the 1986 Census of Canada. Subjects were ail men C-4 = 967) hetwezntJxa~es of45 and 75 yeats resident in the cities of Hamilton ami Salt Stc-h&ie who dial o&utg cater from 1979 to 1988. Conttuls (2,821) mre matched on ape. vearofdeath. and citv of residence In agre&ut with other stti~. &t increased risk of lung cancer was observed for workers in the conauction sector, for miners, and for truck drivers It was estimated that only a small proponion of lung cancers attributable to occupation arc compensated in Ontario. It is believed that many occupational cancets go tmmmpensated because of the failure to tile claims, rather than because claims are rejected by Compensation Boards. Physicians are in a position to advise patients aboul the possibility of mmpensable disease and to act as advocates for them. By recognizing compensable illness, physicians have the opportunity to ease the Iinancial burden of patients and their fanuhes. The challenge is a di5icult one, but it IS well worth pursuing.

Basic biology

Mutations of K-ras oncogene and absence of H-ras mutations in squmnous cell carcinomas oftbe lung Vachtenheim 1, Horakova I, Novotna H. Opalka P, Roubkova H. Laborabxy of Molecular Biology, Inshlvle o/Chest Diseases. 18071 Prague 8. Clin Cancer Res 1995;1:35965.

Mumiotts of the K-ms gene have been implicated in the pathogeuesis of human lung adenocarcinomas. In most studies published so far, squamo”S cell lung cancas halkred l-as mutations only excep+ionally or no mutations were dctated at all. We have examined 141 lungtumor DNA sampks for mutations in cudons 12. 13, and 61 of K-i-as and H- ras oncogenes. A large panel of 118 squamous oell carcinomas was mcluded in the study. For K-as mdon 12, we used a sensttive two-step PCR-restriction fragment hngth polymorphism method which detecur < I%ofmutatedDNA inlhesample. K-msmutalionswerefoundm 17 tumors (12%: I4 in codon li and 3 in codon 13). Among 19 adenocarcinomas. mutation was revealed in 7 samples (37%). Ofthese, one sample harbored tw point mutations in cud& 12. Nine mutational events were found in squamous cell carcinomas (8% one adeno- squamous carcinoma included, all in mdon 12). of four large all carcinomas. one auttained a mutatton. Mutant-enriched PCR pmduaS harboring mutations were dinctly sequenced. Fifteen mutational even6 were Cl T transversiotts or G A transitions. one was a G C transition, and one sample revealed a iiameshit? deletion of one G from wdon 12. Stmilar mutational spectrum was found in both squamous cell carcinomas and adettocarcinomas. suggesting similar carcinogenic pathways in both histological types al the tumor. The presence of mutatum dtd not mnelate with the stage of the disease. Moreover. we analyzed all sample-t for mutations in ccdons 12. 13. and 61 of the H- tas gene. We found only one mutation m codon 12. Thus. H-ras tations apparently play an inferior role in lung catcinogcncsis. We conclude that mutations of the K-ras cmcogene can play a role in the development of not only hmg adenocarcinomas but also of a subset (about 8%) of squamous cell carcinomas.

Voltage-dependent sodium chanoels in human small-cell lune

. Eaton syndrome IgC Blardim JKW, Vlglione MP, Bradley Wh GieHK. Kim Yl Deporrrtenl Biomedrcol Engineering, Unrverstry Virginia School Medrcrne. Chorloftewille, VA 22908. I Membr Bml 1995:143:153- 63

Sodium channels of human smallsell lung cancer (SCLC) cells wereexaminedwith~oleallandsinglechannelpatchclampmelhods In the tumor ~~41s from SCLC cell line NCI-H146. the majority of the voltage-gated Na* chantwls are only wanly tamdotodn o+ensitne (K(d)) = 215 nM). With the membrane potential maintained at -60 to - SO mV. these cells produced all-otwc4hmg action potentials in response todcpolarizingcumnt irjecdon(>ZOpA). Similarall~r-nothmgspikes were also observed with anodal break excitation. Removal of external

Abstracts/Lung Cancer 13 (1995) 81-104

Ca” rbd not a5ect the action potential production, whereas 5 iM TTX or subslttutton of Na* with cholineabolished rt. Action pMentiaIselicited rn the Ca”-free condition were reversibly blocked by 4 mM M&I, due to the Mn”-induced inhibition of voltage-dependent sodium currents (I(Na)) Therefore, Na’ channels, not Ca’* channels, underlie the excitability of SCLC cells. Whole-cell @a) was maximal with step- depolarizing stimulations to 0 mV, and reversed at +45 2 mV, tn accord with the p=dicted Nemst ectuilibrium pofential for a Na+-selective channel. i(Na) evoked by dep&izing test potentials (-60 to +40 mV) exhibited a transient time course and activation/ mactivation kinetics typical of neuronal excitable membranes; the plot oftbe Hodgkin-Huxley parameters. m() and ho. also revealed biophysical similarity between SCLC and neumnal Na’ channels The single channel current amplitude,

the armsense-treated cells compared tith control-treated cells in NCI- H209. Togctkr with unique charaaeristia of the Llnyc gene. including: (a) a frequently amplified and overexpressed state in SCLC; and (b) very rcstictcd and low-level expression in human adult tissues. the present data indicate that L-myc is a good candidate for the target gene for antisenw DNA therapy based on molecular biological diagnosis in SCLC.

as nuasured with the inside-out patch co&guration. was I .O pi at -20 mV with a slope conductance of 12. I pS. The autoantibodies implicated in the Lambert-Eaton myasthenic syndrome (L.ES), whtch are known to inhibit I(Ca) and I(Na) in bovine adrenal chmmaliin cells. also si8niticantly inhibited IlNa) in SCLC cells. These results indicate that (i)action po(endals in human SCLC cells nsult from the regenerative increase in voltage-gated Na* channel conductance: (ii) timdamental characteristics of SCLC Na’ channels are the same as the classical sodium channels found in a variety of excitable cells; and (iii) in some LES patients, SCLC Na’ channels are an additional target of the pathological IgG present in the patients’ sera

Mechmims of MRP over-expression in four human lung-cancer cell lines and analysis of the MRP amplican Eiidems EWHM. De Haa M Ccco-Martin JM. Dttenheim CPE. Zaman &I. DawerseHG et al. &ision Uo/ecu/ar Biology Netherlands Cancer Insdtofe, Plesmanlaan 121, 1066 CYAmstenlam Int I Cancer l995;60:676-84.

Some mtdtidrugresistant cell lines over-express Ihe gene encoding the multidrug-resistann-associaled protein f.MRP). In all all lines reported thus far, over-expression is assccialed with gene amplification. We have studied the predominant mechanisms of MRP over-expression in 4 human Iuwcanccr all lines that myer a range ofdntrrcsistance lewls, and we&e attalyzed the MRP ampli&. In th;SW-l573- derived. waklv resistant cell line 30.3M. h4RP mRNA IS elevated 3- fold in & &s&x of gene amplification. Run-on analysis shows that the increased MRP gene expression in this cell line is due lo trans- criptional activation. In the highly resistant GLC4/ADR and CO&L231 R cells. MRP gene amplification predominates, whereas rn the moderately resistant MOP& alls, geneamplification IS wmbmed with a mechanism nsulting in an additional increase in UK level of MRP mRNA. Fhtomsccnce in situ hybridiratron shows that, in the GLCU ADR cells. amplitied MRP xq!znces arc present both in double minute chromosomes (DM) and in homogeneously stainmg regions (HSR). By pulxd-field gel electrophoresis we show that the MRP-mntaining DM an I Mb in Icngtlt Chromosome-l6-specific repetitive sequences adjacent to the MRP gene arc also present in Ihe DM and HSR, campaliblc with the inwlvement of these sequences in recombination wcnts underlying h4lW gene amphtication. Our results show that low levels of drug resistance may arise by tmnxriptional activatmn of the MRP gene, whereas at high levels of drug resistance amplificalmn of the MRP gene predominates, posslbly facilitated by the prwence of recombination-prone sequences

Inhibition of proliferation by L-myc antisense DNA for the translational initiation site in human small cell lung cancer Dosaka-Akita H, Akie K. Hiroumi H. Kinoshita I. Kawakamr Y, Murakaml A. Fwsl Deparrnwnr of.WedKme. Hokkaido Unrversr~Sch of Bkdrcme. Norlh ,J, Wes, 7. .&to-ku. Sapporn 060. Cancer Res 1995;55 1559-64.

We evaluated the antiprolifera0vc effect of L-myc antisense DNA m NCI- H209. a human small cell lung cancer (SCLC) cell line over- expressing the L- rnyc gene. The syntbetrc DNA used in the present study was oligodeoxynucleoside phospborothiaate, which showed rapid mcorpomtion into NC131209 cells and localized mainly m the cell nucleus and weakly in the cytoplasm. Tbc exposure of this cell line to L-mvc antisense DNA coverina the tnnslational initiation sile of L- myc proteins inhibited the s& proliferation in a dose-dependent seauence-.sccciIic manner. Funhemmre. the mowh inhibitton by this . antscn~ DNA was correlated with the level-of L- myc expression in three SCLC cell lines. NCI-H209, NCI-HS IO. and NCI-H82. In Western blot analysis, expression of the L-myc proteins was down-regulated in

Mutations in the pl6(lNKJ)/MTSl/CDKN2, plS(INKdB)/ MTSZ, and pig genes in primary and metartatic lung cancer Okamoto A, Hussain SP, Hagiwara K, Spillare EA. Ruin MR.

1448-51. We exammed Ihe genomic status ofcychn&pmdent kinase-4 and

-6 mlub~tors, pl6(INK4). pl5(INK4B). and ~18, I” 40 primary lung cancers and 31 metastatic lung cancers Alterations of the p16(INK4) gene were detected in 6 (2 wetirons and 4 homozygous deletions) of 22 metastat~ non-small cell lung cancers (NSCLCs: 27%). but none weredetected in 25 pnmay NSCLCs. 15 primarysmalloell lungcancers (SCLCs). or 9 metastatrc SCLCs. mdrcatin8 that mutation tn Ihe pl6(lNK4) gene IS a late event in NSCLC c&nogenesis Although three mtragenic mutationsofthc pIS(INK4B) gene were dctcctcd fin 25 prrmary NSCLCs (12%) and f,\e homozygous deletions of Ihe olS(INK4Bl eerie wcrc detected tn 22 NSCLCs 123%L no eenetx . _I I

alteratiowofthepl5(INK4B) genewere foundin primary and metastauc SCLCs. The pl8 gene was wdd type tn these 7 I lung cancers. except I metastatic NSCLC whrch showed loss of hetcrwygowy We also esamincdaltcrat1onsofthcrthrcegennandespress~onofpl6(INK4) rn 21 human lung cancer cell hncs. Alteratmns of the plG(INK4) and plS(lNK4B) genes wcredetected I” 7l%ofthe NSCLC cell hnes (n = 14) and 50% of the NSCLC cell hncs (n = l4), rcspect~\cl>. but there

were mane ,n the 7 SCLC cell hnes studwd No plR mutauons were dctcctedmthcsc21 cell hnes Thescraultr~nd~catethatbMhpl6lINK4~ andplS(INKJB)gene mutat,onsareasroc~rtcd~rth tumorprogrcsrmn ofa subset ofNSCLC. but not ofSCLC. and tbat plS(INK4B) mutatwns might also be an early event m the molecular pathogcncsrs of a subset or NSCLC

Increased prevalence of K-w oncogene mutations in lung adenocarcinoma Mills NE, Fishman CL. Ram WN, Dubin N. Jacobson DR. Research Service IJI. New York VA. Hosmlal, 423 E. 23 St.. New York, NY 10010. Cancer Res l995;55 1444-7.

Reported estimates of ras mutation prevalence in lung adeno- carcinomaof l5-24%maybcundexstimatesbecause oftbe insenatrnty of the assays used. We have devised a rapid, non-radioactive assay for ras mutations. which detects I mutant allcle/l0’ normal alleles and have used it to study DNA isolated from 53 lung tunwr samples (including 28 adenocarcinomas) previously analyzed by PCFUallele specific oligonucleotide hybridization, which is less sensitive. We detected m&ions in I3 of 28 samples, including 7 not detected by PCP/alkle so&tic oliaonucleotide hybndwation. We also found ras mutations in.14 of 25 ~wicusly unstudied samples (56%). Our resuits indicate that the prevalence of K-ras codon I2 mutations in lung adenocarciwma is higherthan previously reported; thus, ras mutations may be more clinically use&l as molecular markers for lung cancer than has been appreciated.

Neumlihromntosis type 2 (NF2) gene is somatically mutated in mesothelioma hut not in lung cancer Sekido Y. Pass HI. Bader S. Mew DN. Chnstman MF. Ca&r AF et al Smmons Cancer Centes Umrar.q v/ 7k,r SII Akdtcol (‘rr 5323 Horn Hrnes Bhd, Da//as. T . Y 75235-8590 Cancer Rcs l’J95.55 1227. 31.

WC have found 16 or28 small cell lung carlccrs. I7 or3 I non-llmill cell lung cancers. 2 of 3 carano~ds. and I2 of I4 mcsothclmmas thal had chromosome 22 cymgenetrc abnormalmes To dctcrmme whether the neurofibromalosis type 2 (NF2) gcnc lccalcd on chromosome 22 partic@es m the oncogencsls ofthcsc mahgnanacs. WC studxd DNAs from lung cancer cell lines and mesothclmmas usmg Southern blot analysis and the srnglc-strand conformauon polymorphism (SSCP) techmque for mutations covcrmg 8 of the 16 known NF2 ewns WC