122 Absiracts/ Lung Cancer I2 (199.5) 113-160

Constilutive synthesis of 1,2%Jihydroryvitamin D, by a human small cell lung cancer cell line Mawer EB, Hayes M, Heys SE, Davies M, White A, Stewart MF et al. Universiry Department of Medicine, Manchester Royal Infirmary, OxfordRoad, Manchester A413 9WL. I. Clin Endocrinol Metab 1994; 79:554-60. One of 16 human small cell lung cancer cell lines examined was shown to synthesize a metabolite resembling 1,2Sdihydrox@amin D, [ 1,25- (OH),D,]. The NC1 H82 line converted 2S-hydroxyvitamin D, (25OHD3 into a compound indistinguishable from 1,2S-(OH).D, in 3 different

spectra for the trimethylsilylethers of the metabolite and authentic 1,25- (OH),D, were indistinguishable. Binding to an anti-1,2S<OH),D, antibody was identical for the metabolite and authentic 1,2S-(OH),D, whereas administration to rats in viva caused equivalent stimulation of calcium transport measured in vitro in duodenal sacs. Activity of the H82.16-hydroxylase appears to be substrate dependent and is not stimulated by PTH, suggesting that it is similar to the enzyme expressed by activated macrophages and other cell types at extrarenal sites. Inhibition by ketcconazole indicates that, like the renal and extrarenal enzymes, the H82 enzyme is cytochrome P450 dependent. These data indicate that the H82 small cell lung cancer cell line constitutively expresses 2S-hydroxyvitamin D,-l&hydroxylase and can synthesize l,2S-(OH)ZD,.

RB protein status and clinical correlation from 171 cell lines representing lung cancer, extrapulmonary small cell carcinoma, and mesothelioma Shimizu E, Coxon A, Otterson GA, Steinberg SM. Kratzke RA, Kim YW, Fedorko J et al. Nat1 Cancer In&-Navy OncologvBrnch, Bethesda, MD 20889. Oncogene 1994;9:2441-8. We have studied RB protein expression in 171 cell lines derived from patients with small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), pulmonary carcinoid, mesothelioma, and extrapulmonary small cell cancer (EPSC) and have correlated this data with clinical outcome. We detected absent or aberrant RB protein expression in 661 75 SCLC, 12/80 NSCLC, l/6 carcinoid, O/S mesothelioma, and 4/S EPSC samples. In addition, we observed integration ofhuman papilloma virus (HPV) DNA in the single EPSC cell line that retained wildtype RB protein. We did not detect integration of HPV, SV40 or adenoviral DNA in other tumor samples with wildtype RB status. We also noted a stable, hypophosphotylated mutant RB in 12 SCLC and 3 NSCLC samples which might have been falsely interpreted as wildtype by current immunohistochemical techniques. Analysis of the matched clinical data showed no associations between RB status and age, sex, extent ofdisease, pexformanw status, smoking blstory, and previous treatment. In addition, retrospective analyses showed no consistent correlation of RB protein expression with either best clinical response, overall survival, or in vitro chemotherapeutic drug sensitivity. The stable expression of RB tier gene tram&&on into RB(-) SCLC cells, however, resulted in a trend toward increased in vitro resistance to etoposide, cisplatin and doxorubicin.

p53 expression in normal and dysplastic bronchial epitbelium and in lung carcinomas Walker C. Robertson L.J. Myskow M.W. Pendleton N. Dixon G.R. Clatterbridge Cancer Reseamh Trust, JK Douglas Cancer ReseaEh Lab, Clatterbridge Hospital, Bebington, wirral L63 4JX Br J Cancer 1994;70:297-303. Bronchial epithelial dysplasia is thought to be a premalignant stage in the evolution of lung cancers. Using the CM-l polyclonal antibody, we

have examined the expression of the ~53 protein in a larger series of bronchial dysplasias (n = 60) than hitherto investigated. The pS3 protein was detected in 14% of mikl, 25% of moderate and 59% of severe dysplasias; increased pS3 expression correlated with the severity of dysplasia. pS3-positive dysplasias had greater PCNA indices than pS3- negative dysplasias. pS3 expression in dysplastic tissues was compared with that in two groups of histologically normal epithelium: 14 bronchial biopsies from non-cancer patients of which all but one were negative ad 32 bronchial margins from resected carcinomas, of which 17 showed inl?equent solitary coils with pS3-positive nuclei in predominantly basal locations scattered tbmughout the epithelhun. These results for resection margins were cmfirmed by use of a second antibody, DO-I. Sixty-nine per cent of the corresponding carcinomas were pS3 positive, but in 15 cases the ~53 reactivity differed from resection margins. No correlation between pS3 expression and any ofthe dicopathological characteristics of these tumours was found. This study supports the observation that abnormal pS3 expression may be an early but not obligatory event in malignant transformation in lung.

Alteration in length of telomeric repeats in lung cancer Shirotani Y, Hiyama K, Ishioka S, Inyaku K, Awaya Y, Yonehara S e.t al. Second Dept. of Internal Medicine, Hiroshima Univ. School of Medicine. 1-2-3 Kasutnl, Minami-ku. Hiroshima 734. Lung Cancer (Ireland) 1994; 11:29-4 I, We investigated the relationship between telomere length and various characteristics of tumor cells in 46 lung cancer specimens (40 primary lesions and six metastatic lesions). Three variant patterns of telomere length were observed in I6 cases (34.8%): reduction in 13 cases, elongation in two cases, and convergence in one case. These variant patterns were frequently observed in small cell carcinomas, in metastatic lesions, and in cases which possessed the S-type allele of the L-myc gene. All three cases with telomere elongation or convergence were associated with a poor prognosis. This is compatible with the previous report suggesting that telomerase activity may be an indicator of immortality in vitro. In adenocarcinoma, telomere reduction or elongation was also observed in the early stages with a low percentage of cells in the S-phase, while in cases with other histologic types, these changes were observed only in late stage, in metastatic lesions, or in cancerous tissues with a high percentage of cells in the S-phase. Although the reduction of telomere length in these tissues may be a result of many cell divisions, it may represent another stage of carcinogenesis in early-stage adenccarcinoma.

K-ras gene point mutation: A stable tumor marker in non-small cell lung carcinoma Li S, Rosell R, Urban A, Font A, Atiza A, Armengol P et al. Department of Medical Oncology Univ. Hospital Gennans Trias i Pujol, Box 72, 08916 Badalona, Barcelona. Lung Cancer (Ireland) 1994,ll: 19-27. K-ras gene point mutation is a highly frequent event in human malignancy. About one third of non-small cell lung cancer (NSCLC) patients harbor K-ras gene point mutational activations. This study investigates the prwalence of K-ras mutation in autopsy tumors with NSCLC, and the correlation of K-ras gene point mutations between primary tumors and meta@ses in NSCLC. Formal&fixed, paraffin- embedded tissue sections of 15 primary lung tumors and their meta&ses, (obtained from autopsy), were examined for the presence of point mutations in K-ras gene codon 12, 13 and 61 by oligcdeoxynucleotide hybridization analysis of DNA fragments, amplified by polymerase chain reaction (PCR). K-ras gene point mutations were detected in five cases of lung carcinoma, of which four were adenocarcinomas and one was squamous cell carcinoma. In each of these cases, identical K-ras gene