Electronic Library of Scientific Literature


Volume 44 / No. 3 / 1997

Occurrence of ras mutations in human lung cancer

J. Vachtenhiem

Laboratory of Molecular Biology, Clinic of Pneumology and Thoracic Surgery, University Hospital, 18000 Prague 8 - Bulovka, Czech Republic

Members of ras family of oncogenes, when activated by a point mutation, have been implicated in many types of human cancers. In several types of human solid tumors, point mutations of the K-ras gene are relatively frequent. Among lung cancers, a subset of non-small cell lung carcinomas, mostly adenocarcinomas, contains activated K-ras. The examination of K-ras mutations in samples obtained for diagnostic reasons, such as bronchial biopsies or bronchoalveolar lavage fluid, may be used as a supplement in the early diagnosis of lung adenocarcinoma.

Key words: Lung cancer, K-ras, mutation.
pp. 145-149

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Alcohol intake and risk of breast cancer: The euramic study

M.A. Royo-Bordonada, J.M. Martín-Moreno, E. Guallar, L. Gorgojo, P. van't Veer, M. Mendez, J.K. Huttunen, B.C. Martin, A.F.M. Kardinaal, J. Fernández-Crehuet, M. Thamm, J.J. Strain, F.J. Kok, L. Kohlmeier

Department of Epidemiology and Biostatistics, National School of Public Health, "Instituto de Salud Carlos III", 28 029 Madrid, Spain;
EURAMIC Coordinating Center, Department of Epidemiology and Public Health, Agricultural University of Wageningen. Wageningen, The Netherlands;
Department of Epidemiology and Nutrition, University of North Carolina, Chapell Hill (NC), USA;
Department of Nutrition, National Public Health Institute, Helsinki, Finland;
Institute for Social and Preventive Medicine, University of Zürich, Zürich, Switzerland;
TNO Toxicology and Nutrition Institute, Zeist, The Netherlands;
Departamento de Medicina Preventiva, Universidad de Málaga, Málaga, Spain;
Department for Health Risks and Prevention, Robert Koch Institute, Berlin, FRG;
Human Nutrition Research Group, University of Ulster, Coleraine, Northern Ireland

To evaluate the association of alcohol intake with the risk of breast cancer in post-menopausal women, we analyzed the data from an international case-control study conducted in five European countries (FRG, Switzerland, Northern Ireland, the Netherlands and Spain). Information on alcohol intake was available in 315 cases and 364 controls. Medians for the tertiles of alcohol intake among current drinkers were 1.7, 6.0, and 20.0 g/day. Adjusted relative risks (and 95% confidence intervals) of breast cancer for each tertile of intake in current drinkers, compared to never drinkers, were 1.00 (0.60-1.67), 1.01 (0.60-1.73), and 1.18 (0.69-2.03). The adjusted relative risk for ex-drinkers was 1.73 (1.07-2.79). Among both current drinkers and ex-drinkers, the relative risk was higher for those with body mass index above the median compared to those with body mass index below the median. These results do not support a dose-response effect of alcohol on breast cancer risk, although consumption levels were too low to exclude increased risk with high regular intake. Further research is necessary to evaluate the risk of developing breast cancer among ex-drinkers and the potential interaction between body mass index and alcohol drinking.

Key words: Breast cancer, alcohol, case-control studies.
pp. 150-156

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Characterization of human breast adenocarcinoma SK-BR-3 cells resistant to doxorubicin

M. Osmak, S. Kapitanoviæ, I. Vrhovec, L. Beketiæ-Oreškoviæ, B. Jernej, D. Eljuga, J. Škrk

Department of Molecular Genetics, Ruðer Boškoviæ Institute, 10 000 Zagreb, Croatia;
Department of Molecular Medicine , Ruder Bokšoviæ Institute, Zagreb, Croatia;
Department of Radiobiology, Institute of Oncology, Ljubljana, Slovenia;
Department of Gynecology, University Hospital for Tumors, Zagreb, Croatia

Doxorubicin shows a wide spectrum of activities in solid tumors, especially against breast carcinoma. The aim of this study was to examine if doxorubicin, when given at lower concentrations than applied in clinic, may induce changes in treated cells. With this purpose we developed human breast adenocarcinoma SK-BR-3 cell line resistant to doxorubicin. The sensitivity of these cells to doxorubicin and to some other cytostatics used in cancer treatment was determined by colorimetric MTT assay. Some parameters which may be of importance as prognostic factors in treatment of breast cancer were analyzed as well. The expression of genes involved in mitotic signal pathway (EGF, TGFalpha, EGF-R, erbB-2, erbB-3, c-myc and c-H-ras) was determined immunocytochemically. The concentrations of cathepsins were determined using quantitative immunoreactive assays (cathepsins B and L) or immunoradiometric assay (cathepsin D). The results revealed that even low doses of doxorubicin can induce numerous changes in treated cells: they become resistant to doxorubicin, and cross-resistant to several other cytostatics. The expression of the above mentioned genes involved in mitotic signal transduction, as well as cathepsins D and L, was similar in both parental and doxorubicin treated cells.

Key words: Doxorubicin, breast adenocarcinoma, cell cultures, drug resistance, cathepsins, mitotic signal transduction.
pp. 157-162

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Prognostic significance of tumor angiogenesis in advanced breast carcinoma: An indian experience

N.H. Karelia, D.D. Patel, D.B. Balar, N.S. Desai, S.U. Patel, K. Dave, G.B. Shah

Department of Pathology Oncology, The Gujarat Cancer and Research Institute, New Civil Hospital Compound, Asarwa, Ahmedabad, 380 016 India;
Department of Surgical Oncology, The Gujarat Cancer and Research Institute, New Civil Hospital Compound, Asarwa, Ahmedabad India

Angiogenesis is essential for tumor growth and metastasis. In the present study we investigated the prognostic significance of microvessels (MV) density using immunohisto-localization of factor VIII antigen in 51 breast cancer patients. We counted microvessels per 200x field in the most active areas of neovascularization by staining factor VIII related antigen and graded MV density and correlated with stage, LN involvement and histologic grade. Patients who subsequently developed metastases had significantly high MV counts than patients without metastatic disease (p < 0.001). Patients who subsequently died of the disease had significantly high mean microvessels counts than patients who remained alive at the end of 5 years (p < 0.001). As density of factor VIII antigen staining increased the survival decreased (p < 0.001). All the patients having >25 MV per 200x field had tumor recurrence faster as compared with patients having <25 MV (p < 0.02). Thus, the MV count correlates with the prediction for metastasis and poor survival. Such an indicator would be useful in selection of a subgroup of patients with breast cancer who are at high risk for having occult metastasis at presentation and subsequently would benefit from aggressive therapy.

Key words: Breast cancer, angiogenesis, prognosticator.
pp. 163-166

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Surfactant system in lung cancer
Endogenous lipid pneumonia

M. Sulkowska, S. Sulkowski, L. Chyczewski, J. Nikliñski

Department of Pathological Anatomy, University Medical School of Bia³ystok, PL 15-269 Bia³ystok, Poland;
Department of Thoracic Surgery, University Medical School of Bia³ystok, Poland

The aim of the study was the evaluation of endogenous lipid pneumonia-type changes developing in the vicinity of primary tumors of the lungs. The postoperative material collected from 56 patients operated for non-small cell lung cancer was examined. The coexistence of endogenous lipid pneumonia-type changes with squamous cell carcinoma and large cell carcinoma of the lung was most common. Patients with these histopathological types of carcinoma had lower percentage of metastases to the lymph nodes. Endogenous lipid pneumonia was found to accompany most frequently the tumors 3 =< 6 cm in diameter and it was slightly more common in the vicinity of peripheral tumors.

Key words: Lung cancer, endogenous lipid pneumonia.
pp. 167-171

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Taxol-enhanced cytotoxic effect of radiation in human promyelocytic leukemia cells: Relative resistance of multidrug-resistant HL-60 cells in vitro

J. Sedlák, M. Šuliková, M. Chorváth, ¼. Hunáková, L. Novotný, V. Laginová, ¼. Ševèíková, E. Bolješiková, B. Chorváth

Cancer Research Institute, 812 32 Bratislava, Slovakia;
Department of Radiotherapy, St Elisabeth Cancer Institute, Bratislava, Slovakia;
Postgraduate Medical School, Bratislava, Slovakia

Cytotoxic effects of sequential taxol (paclitaxel) and X-irradiation on drug-sensitive human cultured promyelocytic leukemia (HL-60) cell line and its multidrug-resistant sublines were examined using photometric MTT test and flow cytometry. Paclitaxel (at concentrations 1-10 nmol) stimulated the cytotoxic effect of irradiation in HL-60 and to a lesser extent also in HL-60/ADR, but not in HL-60/VCR cells. The stimulation of radiation-induced cytotoxic effect by paclitaxel correlated with its potential to induce cell cycle and viability alterations identified with flow cytometric analysis (i.e. increased propidium iodide staining, increased side scatter, decreased forward angle scatter, accumulation of necrotic cell detritus, apoptotic pre-G0 cells and cells in the G2/M phase of the cell cycle).

Key words: Multidrug-resistance, taxol (paclitaxel), human promyelocytic leukemia, HL-60/VCR - HL-60/ADR - MDR-1 - MRP - MTT test, flow cytometry, cell cycle analysis.
pp. 172-177

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Distribution and photodynamic effect of zinc phthalocyanine disulfonate in nude mice bearing mammary carcinoma

M. Moša, M. Zitko, P. Pouèková

Institute of Biophysics, First Medical Faculty, Charles University, 120 00, Prague 2, Czech Republic

The distribution study of zinc phthalocyanine disulfonate (ZnPcS2) in nude mice bearing mammary carcinoma (T50/80) revealed a rapid uptake of the dye by tumor.
In experimental photodynamic therapy (PDT), the tumors were exposed to laser radiation (670 nm, 100 mW/cm2, 150 J//cm2) after intravenous administration of ZnPcS2 in saline. The results showed the maximum tumor destruction to be achieved for the time interval between injection of the drug (2 mg/kg) and exposure to laser light of 5 min, while a significantly less damage was observed when the time interval was 24 h (p < 0.0001).
The degree of damage produced by the treatment was monitored in vivo by means of noninvasive NMR-imaging and subsequently confirmed histologically.

Key words: Photodynamic therapy, tumor necrosis, nude mice, zinc phthalocyanine disulfonate, NMR-imaging.
pp. 178-183

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Effects of intracellular chelatable iron and oxidative stress on transcription of classical cellular glutathione peroxidase gene in murine erythroleukemia cells

O. Fuchs

Institute of Hematology and Blood Transfusion, 128 20 Prague 2, Czech Republic

The effect of intracellular chelatable iron levels and of oxidative stress on nuclear classical cellular glutathione peroxidase (GSHPx-1) RNA nascent chain elongation (run-on transcription) and on the stability of cytoplasmic GSHPx-1 mRNA was investigated in murine erythroleukemia (MEL) cells. The amount of iron in the intracellular low molecular mass iron pool was changed by incubation of MEL cells transformed by Friend virus with iron donors or iron chelators. Transcription in vitro in isolated nuclei from treated cells showed that the treatment with iron chelators (desferrioxamine (DFO), pyridoxal isonicotinoyl hydrazone (PIH)) decreased the rate of nuclear GSHPx-1 RNA nascent chain elongation in both uninduced and with 5 mmol hexamethylenebisacetamide (HMBA) to erythroid differentiation induced MEL cells. Iron donors (diferric transferrin, Fe-PIH or their combination) and t-butyl hydroperoxide (t-BuOOH) had the opposite effect on GSHPx-1 gene transcription in run-on experiments. On the other hand, 50 µmol DFO or 2.5 µmol t-BuOOH did not change the stability of cytoplasmic GSHPx-1 mRNA in both uninduced and induced MEL cells treated with 5 µmol actinomycin D and with or without these agents for 9 h. These findings indicate that iron and oxidative stress play their role at the transcriptional level of GSHPx-1 gene expression.

Key words: Classical cellular glutathione peroxidase mRNA, iron chelators, iron donors, oxidative stress, murine erythroleukemia cells.
pp. 184-191

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In vivo tumor necrosis factor-alpha induction following chlorin e6 - photodynamic therapy in Buffalo rats

P. Zió³kowski, K. Symonowicz, J. Milach, B. Zawirska, T. Szkudlarek

Department of Pathology, Medical University of Wroc³aw, 50 368 Wroclaw, Poland

Photodynamic therapy may induce in the in vivo conditions the cytokine tumor necrosis factor-alpha in Buffalo rats. The sensitizer, i.e. chlorin e6, in the doses 2.5, 5.0 and 7.5 mg/kg of body weight followed by light treatment with total doses 50, 100, 150, 200 and 250 J/cm2 resulted in the increase of serum levels of the cytokine. The levels of tumor necrosis factor-alpha have been determined at different time points using enzyme-linked immunosorbent assay (ELISA). In control animals these levels did not exceed the mean value of 189 pg/ml, whereas in photodynamically treated rats the levels were almost 3-4 times higher. The entire experiment has been carried out on healthy animals; control, tumor-bearing rats have also been included to the present experiment.

Key words: Photodynamic therapy, chlorin e6, tumor necrosis factor-alpha.
pp. 192-196

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Chloroaceto hydroxamic acid as antitumor agent against Ehrlich Ascites carcinoma in mice

P. Sur, S.P. Bag, B. Sur, J.A. Khanam

Division of Pharmacology, Indian Inst. of Chemical Biology, Calcutta 700 032, India;
Department of Chemistry, Jadavpur University, Calcutta 700032, India

In vivo cell growth inhibition of Ehrlich ascites carcinoma (EAC) has been evaluated with chloroacetohydroxamic acid, (CHA), having -CH2 Cl, for the -NH2 group of hydroxyurea (HU). The inhibitory character of CHA against EAC in mice model has been found to be comparable with that of HU. Cell growth inhibition by CHA is accompanied by inhibitions of DNA and protein synthesis of the treated cells. The transplantability of EAC cells treated with a single dose of (100 mg/kg) CHA is found to be reduced. Enhanced intraperitoneal macrophage is observed in normal mice following CHA (100 mg/kg) treatment. Deviations of hematological parameters and alkaline phosphatase (ALKP) activity consequent to tumor growth are found to be recovered in tumor bearing mice treated with CHA. All these studies suggest the importance of CHA for further trial as a potent antitumor agent.

Key words : CHA, EAC, antitumor activity, hematology.
pp. 197-201

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Apoptosis update: To be, or not to be, and how to arrange the latter
Meeting review

M.A. Sheard

Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic

It has become accepted that cell death is an essential mechanism for the maintenance of an animal's health. But how do cells know when they should die, and how do they do it? A recent conference titled "Programmed Cell Death" was held by the American Association For Cancer Research in Bolton Landing, New York state, USA, on October 19-23, 1996, which focused on the signals that push a cell towards its own self-destruction, and also on the biochemical tools used by these cells in making this ultimate sacrifice.
The molecular vocabulary of programmed cell death is only recently being deciphered. At the heart of programmed cell death exists at least one intrinsic program for committing cell suicide, although it is still unclear if there is only one [3]. If only one program exists, it probably contains multiple branches, overlapping pathways, and redundant molecular interactions. One item is clear, however: there exist many mechanisms for inducing cells to suicide.

pp. 202-204

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