Chemopreventive properties and mechanisms of N-acetylcysteine. The experimental background

152

Abstracts

/Lung

Association of body mass index and body fat distribution risk of lung cancer in older women

Cancer

with

Drinkard CR, Sellers TA, Potter JD, Zheng W, Bostick RM, Nelson CL et al. Division ofEpidemiology, School ofPublic Health. University of Minnesota. 1300 South Second Street, Minneapolis, MN 55454-1015. Am J Epidemiol 1995;142:600-7. Obesity has been associated with an increased risk of cancer at a number of sites. A notable exception appears to be lung cancer, for which several studies suggest a modest inverse association. However, cigarette smoking is directly associated with lung cancer and inversely associated with body mass index. To investigate the hypothesis that body mass index is associated with lung cancer independent of cigarette smoking, the authors analyzed data from a prospective cohort study of 4 1,837 Iowa women aged 55-69 years at baseline in 1986. In addition, they examined whether central adiposity (high waist/hip ratio) was associated with lung cancer incidence. Through 1992 (6 years offollowup), 233 cases of lung cancer were identified through the State Health Registry of Iowa. The body mass index at several ages was calculated from self-reportsofheight at baseline and weights at ages 18,30,40, and 50 years and at baseline. Current and former smokers generally had lower mean body mass indices than did nonsmokers at all ages except 18years. Casesgenerallyhadlowerbodymassindicesthandidnoncases at all ages except I8 and 30 years but. among current smokers, cases had higher mean body mass indices than did noncae-s at all ages except baseline, although the differences were not statistically significant. An apparent positive association of a high waist/hip ratio with lung cancer in the total cohort was found to be primarily accounted for by a higher waist/hip ratio in current and former smokers. When stratified by smoking status and adjusted for other risk factors, including age and pack-years of smoking, the body mass index at baseline, body mass index at age 50 years, and waist/hip ratio were not associated with lung cancer. The results of multivariate analyses suggest that the inverse association of body mass index with lung cancer can be explained by smoking status and that the positive association of waist/hip ratio with lung cancer can be explained by pack-years of smoking.

Chalcones, myo-inositol and other novel inhibitors pulmonary carcinogenesis

of

The objective of the studies reported here has been to find novel chemopreventiveagentseffectiveagainstcarcinogenesisofrlle lung. In particular, identification of suppressing agents. i.e.. compounds preventing the evolution ofthe neoplastic process, has been sought. For this purpose, inhibition of pulmonary neoplasia in female A/J mice given the test agent starting one week aAer the last administration of three doses of benzo[a]pyrene has been employed as the experimental model. Under these conditions. chalcone. 4’-methoxychalcone. myoinositol. dexamethasone, and ‘terpeneless’ orange oil added to the diet suppressed pulmonary adenoma formation. Chalcone and 4’methoxychalconeareopenchainflavonoids,neitherofthesecompounds occurs naturally. and their mechamsm of action is not known. myoInositol isanaturallyoccurringcompoundofparticularinterest because of its exceedingly low toxicity. Dexamethasone is a potent glucocorticoid. Amongst irs biological properties is the capacity 10 induce maturation of Type 2 alveolar cells and to stimulate production of surfaclam by these cells. ‘Terpeneless’ orange oil is a fraction oforange oil consisting predominantly of compounds with carbonyl or hydroxyl groups. The constituent or constituents responsible for the inhibitory effects observed is not known, The above studies are in an early phase of development and their ramifications remain to be determined.

14 (19%)

149-179

N-acetylcysteine (NAC) and glutathione (GSH): Antioxidant and chemopreventive properties, with special reference to lung cancer Van Zandwijk N. Department of Chest Oncology, Nederlands Kancer Institute, Plesmanlann 121. 1066 CX Amsterdam. J Cell Biochem 1995;58:Suppl22:2432. Lung cancer arises as a focal transformation of chronically injured epithelium with cigarette smoke as one of its well-recognized causes. Apart from oxidants (free radicals), cigarette smoke contains such a multitude of @re)carcinogens that it is astonishing that not every heavy smokerbecomesavictimofmalignancy.?hispointstotheinterindividual variability in susceptibility to carcinogens; several lines of evidence suggestthatmetabolic factorsareinvolvedinsuchvariability. Metabolism of carcinogens as well as the subsequent (multi)steps of carcinogenesis are affected by host factors and governed by the balance between opposing forces, such as metabolic activation and detoxification, formation and scavenging of radicals, and DNA damage and repair, which seem to imply that carcinogenic compounds can initiate tumor growth only in amounts saturating detoxification mechanisms. In this context it is well known that glutathione (GSH) plays a crucial role in thedetoxiftcationofxenobiotics.N-Acetylcysteine(NAC),anaminothiol and synthetic precursor ofintracellular cysteine and GSH, has been used formany yearsin Europeasamucolyticdmg. Clinically,it isasafeagent without major side effects and has been considered to have a place in cancerprevention,too.~eantimutagenicandanticarcinogenicpropenies of NAC could be ascribed to multiple protective mechanisms, such as NACnucleophilicity,antioxidantactivity.itsabilitytoactasaprecursor of intracellular reduced GSH, modulation of detoxification, and DNA repair processes. On these grounds, NAC has emerged as a most promising cancer chemopreventive agent. Since 1988, NAC has been tested in a large European chemoprevention study (EUROSCAN) mvolving high risk Individuals to prevent the occurrenc,e of a second primary (lung) cancer. Toxicity data of this and other studies confirm that a long-term dally usage of NAC in a 600 mg dose is safe, and may be recommended for clinical chemopreventive research.

Chemopreventive properties and mechanisms of N-acetylcysteine. The experimental background De Flora S, Cesarone CF. Balansky RM, Albini A, D’ Agosrini F. Bennicelli C et al. iwt. of ~~giene/J’reventive Medicine. University q/‘ (irrrou. Via Pustore I. l-16132 Genoa. J Cell Biochem 1995;58:Suppl 22:33-41. The thiol N-acetylcysteine (NAC),now under clinical trial for cancer chemoprevention both in Europe (project Euroscan) and in the US (National Cancer Institute). has been shown during the past decade to exert protective effects in a variety of experimental test systems. NAC inhibited spontaneous mutagenicity and that induced by a number of chemical compounds and complex mixtures. Moreover, NAC significantly decreased the incidence of neoplastic and preneoplastic lesions induced by several chemical carcinogens in rodents (mice, rats, hamsters), e.g., in lung, trachea, colon, liver, mammary gland, Zymbal gland, bladder and skin. Our studies provided evidence that multiple mechanismscontributetoNACantimutagenicityandanticarcinogenicity. They include extracellular mechanisms, such as detoxification of reactive compounds due to the nucleophilic and antioxidant properties of NAC. inhibition of nitrosation products, and enhancement of thiol concentration inintestinal bacteria;trappingandenhanceddetoxification of carcinogens in long-lived non-target cells, such as erythrocytes and bronchoalveolar lavage cells; mechanisms working in the cytoplasm of target cells, such as replenishment of GSH stores, modulation of metabolism of mutagens/carcinogens, blocking of electrophiles, and scavenging of reactive oxygen species; and nuclear effects, such as

Abstracts

/Lung

Cancer

inhibition of DNA adduction by metabolites of carcinogens. inhibition of ‘spontaneous’ mutations, attenuation of carcinogen-induced DNA damage, and protection of nuclear enzymes, such as poly(ADP-ribose) polymerase. In particular, benzo(a)pyrene diolepoxide-DNA adducts in rats exposedeither tobenzo(a)pyrene or cigarette smoke were prevented by NAC not only in target organs for carcinogenicity, such as lung and trachea, but also in other organs, such as heart, aorta and testis, where these molecular biomarkers have been tentatively associated with cardiomyopathies, atherosclerosisand hereditary diseases, respectively. The protective mechanisms of NAC are expected to affect not only initiation but also promotion and progression, due to the reiterate involvement of certain key mechanisms in carcinogenesis. Moreover, recent studiesdemonstrate that NAC can also affect the stepsof invasion andmetastasis. includingthe specific inhibitionoftype IV collagenases degrading basement membranes, inhibitionofchemotacticand invasive activities of human and murine malignant cells, delay ofprimary tumor formation inmice, and inhibitionoflungmetastases. Evidence wasalso provided that administration ofpharmacological doses ofNAC sharply decreases urinary excretion of mutagens in smokers.

Basic biology Occupational

risk factors for lung cancer in Tianjin, China

Wang Q-S, Boffetta

P, Parkin

Research

IS0 cows

on Cancer,

DM, Kogevinas Albert

Thomas,

M. IntI. Agency 69372

Lyon

Cedex

for 08.

Am J Ind Med 1995;28:353-62. Information about occupation and industry of cancer patients is routinely recorded in the Cancer Registry ofTianjin, People’s Republic ofChina.Occupationalriskfactorsoflungcancerfortheperiodof 19811987 were assessedusingother cancersascontrols. For each occupation and industry, workers employed in it were considered exposed and were compared with all otherworkers. Elevatedrisks were found foranumber of industries for both sexes, including, in particular, the textile, wood, metal, and construction industries. Results by occupation were similar to those by industry. Smoking scores were calculated for various occupations on the basis of a separate population survey in Tianjin. Smoking cannot explain the elevated odds ratios in males, while among females a strong correlation was observed between smoking scores and lung cancer odds ratios, suggesting a confounding effect.

Dissemination in athymic nude mice of IacZ transfected small cell lung cancer cells identified by X-gal staining Romer MU, Christiansen Pathological

Anatomy,

J, Brunner Fredetik

Vs

N, Spang-Thomsen Vej II,

DK-2100

M.

Inslilute

Copenhagen.

APMIS 1995;103:582-7. The small cell lung cancer cell lines GLC-2 and DMS 456 were genetically labeled with the IacZ gene and examined for invasive and metastatic potential in META/Bom(TM) nude mice. The 1acZ gene encodes the enzyme g-D-galactosidase, and cells expressing this enzyme was identified by staining with the chromogenic substrate X-gal. 1acZ expressing cells were investigated after subcutaneous (s.c.) inoculation andintravenous(i.v.)injection.TheX-galdetectionof0-D-galactosidase activity proved to be a rapid and easy means for specific and highlysensitive identification ofmetastases. All primary S.C. tumors stained by X-gal. The primary tumors of GLC-2 regularly demonstrated local invasive growth and producedmultiple metastases in several organs. In contrast, primary DMS 456 tumors only occasionally demonstrated localinvasionandveryrarelygenetatedsecondaryfoci.Noexperimental metastases were found after iv. injection of the examined tumor lines.

I4

( 1996)

I49-

I79

153

The results indicate an intratumoral heterogeneity among individual SLC tumors in the capacity for invasion and metastatic spread The different metastatic patterns of GLC-2 after S.C. and i.v. inoculation support the hypothesis that initial steps of the metastatic cascade occurring in the primary tumor are necessary for the subsequent production of growing metastases.

Altered expression of the p50 subunit of the NF-kappaB transcription factor complex in non-small cell lung carcinoma Mukhopadhyay Oncologv. Anderson

T, Roth JA, Maxwell

Dept Cancer

Thoracic Center,

SA. Section Thoracic Molecular Cardiovascular Surgery. Univ Texas MD Houston, TX 77030. Oncogene 1995; I I :999-

1003. Recent studies have implicated a role for the ~50 subunit ofthe NFkappaB transcription factor complex in tumotigenesis. Therefore, we investigated the expression of the ~50 subunit of the NF-kappaB transcription factor complex in paired normal and non-small cell lung carcinoma (NSCLC) tissues. Here we showthat nine of 11(8 1.8%) fresh NSCLC tissues expressed from two- to 20-fold higher levels ofthe ~50 subunit than normal lung tissue. Thirteen NSCLC cell lines also exhibited high levels of p50. Alterations in the normal NF-kappaB/rel pathway of regulation may play a role in the genesis of NSCLC.

A hereditary genetic marker closely associated with microsatellite instability in lung cancer Ryberg Toxicology,

D, Lindstedt

BA, Zienolddiny

Natl. Inst. of OccupationalHealth.

S, Haugen A. Department P.O. Box8149,

of

N-0033

Oslo. Cancer Res 1995;55:3996-9. Alterations in 5 microsatellite loci were analyzed in tumors from I37 patients with primary non-small cell lung carcinomas that were also genotyped for the I-has1 variable number of tandem repeats (VNTR) locus. Twenty-nine patients (2 I%) had changes in at least one microsatellitelocus. Amajorityofthesecases(24of29,83%)hadVNTRalleles classified as rare in the population. The frequency of these rare alleles were significantly higher among lung cancer patients than in healthy controls (P = 0.016 or 1.80: 95% confidence interval = 1.13-2.85). Microsatellite alterations were significantly more frequent among patients with at least one rare I-has1 VNTR allele (24 of 40, 60%) compared to patients with two common alleles (5 of 97,5%; P < 0.00 I or27.6;95%contldenceinterval=8.18-82.9). Microsatellitealterations were also more frequent among patients below 50 years of age (8 of 2 I, 38%) than for older patients (21 of 112, 19%).

Coexpression pattern of c-myc associated genes in a small cell lung cancer cell line with high steady state c-myc transcription Dooley

S, Wundrack

I, Blin N, Welter

C. Department Geb 68. 66421 Homburg.

of Human

Biochem Biophys Res Commun 1995;213:789-95. The c-Myc protein is involved in cellular transformation and mitogenesis, but also works as a potent inducer of differentiation and programmed cell death. Max as an obligate heterodiietic partner for Myc mediates its functions as a specific transcriptional activator and a transforming protein. Mad and Mxi I proteins both heterodimetize with Max and compete with each other for limiting amounts of Max. Transcriptional activation by Myc can be suppressed by increasing the amount of Mad or Mxi 1. This report shows the expression pattern of these Myc related factors at the mRNA level in a small cell lung cancer (SCLC) cell line (GLC4) which is characterized by c-myc amplification and strong constitutive c-myc overexpression. We found these genes transcriptionally active but uninfluenced from high c-myc transcription. Genetics,

University

of Saarlond.