Electronic Library of Scientific Literature


Volume 47 / No. 1 / 2000



Tamoxifen in cancer therapy - Minireview

L. Novotný, P. Rauko, A. Vachálková, M. Peterson-Biggs

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait; e-mail: novotny@hsc.kuniv.edu.kw;
Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovak Republic;
Pharmaceutical and Herbal Medicines Registration and Control Administration, Ministry of Health, Safat, Kuwait

Tamoxifen belongs among relatively new drugs. As it has already been shown, it undoubtedly brings a benefit to oncology patients. However, there are still questions regarding its broader use in therapy or cancer prevention. This review puts together some data available at present time with the aim of elucidating the most important aspects of its use in medical oncology.

Key words: Tamoxifen, cancer, gynecology.
NEOPLASMA, 47, 1, 2000, 3-7


Immunohistochemical analysis of expression of a 65 kDa oncofetal protein (p65), epidermal growth factor receptor (EGFR), oncogene c-erb B2 and tumor suppressor gene p53 protein products in breast cancer patients

H. Niewiadomska, M. Mirowski, M. Stempień, J.Z. Błoński, W. Czyż, J. Świtalska, E. Matyga, M. Hanausek, R. Wierzbicki

Department of Oncology, Medical University, Lodz, Poland;
Department of Surgery, Oncological Center of Lodz, Poland;
Department of Hematology, Medical University of Lodz, Poland;
Department of Endocrinologic Surgery of Lodz, Poland;
Department of Biochemistry, Institute of Environmental Research and Bioanalysis, Medical University, 90-151 Lodz, Poland; e-mail: mirowski@ich.pharm.am.lodz.pl;
Radioisotope Center Polatom Otwock-Świerk, Poland;
AMC Cancer Research Center, Denver, Colorado, USA

Paraffin-embedded tissue slides from 88 infiltrating ductal breast carcinoma were examined by immunohistochemistry technique with the use of monoclonal antibody against human p65 antigen and polyclonal antibody against p65-like protein present in fetal bovine serum. Immunohistochemical analysis of expression of growth factor receptors (EGFR), protein product of oncogene c-erb B2 as well as protein product of mutated anti-oncogene p53 was also done. It was established that there is no correlation between p65 and c-erbB2, EGFR or p53 expression. In low differentiated tumors (grade III) high p53 index and high EGFR and c-erbB2 expression was connected with low p65 expression. The lack of c-erbB2 and EGFR and low p53 expression was combined usually with high p65 oncoproteine levels.

Key words: p65 oncofetal protein, c-erbB2, p53, EGFR and breast cancer.
NEOPLASMA, 47, 1, 2000, 8-14


Influence of estrogen, antiestrogen and UV-light on the balance between proliferation and apoptosis in MCF-7 breast adenocarcinoma cells culture

J. Świątecka, J. Dzięcioł, T. Anchim, M. Dąbrowska, M. Pietruczuk, S. Wołczyński

Institute of Gynecology and Obstetrics, Medical University of Białystok, Białystok 8, 15-276, Poland; jswia@amb.ac.bialystok.pl.;
Department of Pathological Anatomy, Medical University of Białystok, Poland;
Department of Gynecological Endocrinology, Medical University of Białystok, Poland;
Department of Hematological Diagnostics, Institute of Laboratory Diagnostics, Medical University of Białystok, Poland

Studies of the mechanism of actions of estrogen, antiestrogen and physical factors may provide clues to an understanding of breast cancer growth and/or regression regulation and thus identify novel targets for therapeutic intervention. Defective control of apoptosis appears to play a central role in the pathogenesis of neoplasia. Conversely, cancer therapy and ionizing radiation can induce cancer cell death by apoptosis and/or necrosis. bcl-2 gene and p-53 gene products have been both linked to programmed cell death pathways. We have analyzed the effect of estradiol, tamoxifen and UV exposure on the induction of apoptosis, expression of p53 and bcl-2 gene products as well as the proliferative activity (expressed as [3H]thymidine incorporation and PCNA and MPM2 antigens involvement) in MCF7.
It has been found that estradiol increases the speed of cell cycle in MCF7 and acts as antiapoptotic factor. Tamoxifen has multiple influence on the rate of growth of cancer cells: depends on estrogen receptor (ER), conducts reduction of proliferation rate; depends on ER and other mechanisms conducts to suppressions of Bcl-2 protein expression and induction of cell death through apoptotic pathway. Estradiol prevents the apoptotic influence of tamoxifen probably by enhancement of Bcl-2 protein expression and does not prevent the inhibition of proliferation rate. The irradiation with UV induces apoptosis by over-expression of p53 and down-regulation of bcl-2 gene.

Key words: Apoptosis, breast cancer, estradiol, MCF-7 cells, proliferation, tamoxifen, ultraviolet.
NEOPLASMA, 47, 1, 2000, 15-24


Radiation-induced apoptosis and cell cycle alterations in human carcinoma cell lines with different radiosensitivities

Ľ. Hunáková, M. Chorváth, J. Duraj, Z. Bartošová, Ľ. Ševčíková, M. Šuliková, J. Chovancová, J. Sedlák, B. Chorváth, E. Bolješíková

Cancer Research Institute, Slovak Academy of Sciences, 833 91 Bratislava, Slovak Republic;
Department of Radiotherapy, St Elisabeth Cancer Institute, Bratislava, e-mail: exonhun@savba.sk

Radiosensitivity of examined human neoplastic cell lines was assessed with the aid of MTT assay. Differences between radiosensitive and radioresistant human neoplastic cell lines were as follow: a) radiation-induced apoptosis detected by flow cytometry was apparent in the most radiosensitive (i.e. CH-1 ovarian carcinoma cell line), but not in the radioresistant (i.e. SKOV-3 ovarian carcinoma) cell lines, b) radiation-induced G2/M arrest appeared early after irradiation (6 hours) in both the radioresistant SKOV-3 cells and in the radiosensitive CH-1 human ovarian carcinoma cell line, but a different pattern was observed 24 hours after irradiation with 2 Gy dose with G2/M arrest only in radiosensitive cell line. The radiosensitivity and resistance to radiation-induced apoptosis in the radioresistant human breast carcinoma MDA-MB-231 cell line were similar to those observed in SKOV-3 cells. These data suggest that radiation-induced apoptosis and cell cycle alterations can predict radiosensitivity at least in some examined human malignant cells in vitro.

Key words: Human breast and ovarian carcinoma, cell lines, ionizing irradiation, apoptosis, cell cycle alterations, flow cytometry, MTT assay, radiosensitivity, PARP cleavage.
NEOPLASMA, 47, 1, 2000, 25-31


Effect of epinephrine and combination treatment of epinephrine and heat on melanoma cell lines. Study of cytotoxicity and kinetics of 72-kD stress protein

M. Hatoko, A. Tanaka, M. Kuwahara, H. Tada, T. Ohnishi, T. Muramatsu

Division of Plastic Surgery, Nara Medical University, Kashihara City, Nara, 634-0813, Japan;
Department of Dermatology, Nara Medical University, Kashihara City, Nara, Japan;
Department of Biology, Nara Medical University, Kashihara City, Nara, Japan e-mail: mhatoko@nmu-gw.naramed-u.ac.jp

To elucidate the effect of epinephrine and the combination with heat on malignant cells, using two melanoma cell lines, HM6KO and G361, we have examined the cytotoxicity and induction of 72-kD stress protein (HSP72) after the treatments. After epinephrine treatment, in both cell lines, cell survival rates decreased gradually in a concentration-dependent manner. After the combination treatment, cell survival rates decreased more than those when two treatments were done separately. The cytotoxicity of epinephrine was more enhanced in G361 than in HM6KO by heat.
After epinephrine treatment, in both cell lines, the level of HSP72 did not elevate. After combination treatment, in HM6KO, the level of HSP72 were higher than those of heat alone. In G361, the kinetics of HSP72 level was similar to that of heat alone.
These results suggest that epinephrine has a cytotoxicity to melanoma cells and the cytotoxicity is enhanced by the combination.
In addition, it is probable that epinephrine does not have HSP72 inducibility in HM6KO and G361, and the different kinetics of HSP72 between the cell lines in the combination treatment may play an important role to determine the degree of enhancement.

Key words: Epinephrine, HSP72, stress protein, hyperthermia, melanoma.
NEOPLASMA, 47, 1, 2000, 32-36


Blood levels of natural antioxidants in gastric and colorectal precancerous lesions and cancers in Slovakia

I. Beňo, J. Klvanová, T. Magálová, A. Brtková

Research Institute of Nutrition, 833 37 Bratislava, Slovak Republic; e-mail: beno@vuv.sk

A long-term sufficient intake of fruits and vegetables reduces significantly the risk of gastric and colorectal carcinoma. It is anticipated that natural antioxidants are involved in this effect in addition to other substances. The aim of this study was to determine levels of vitamins A, C and E, as well as beta-carotene, selenium, zinc and copper in blood of 249 patients with precancerous lesions (atrophic gastritis, gastric hyperplastic polyp, gastric, colonic and rectal adenoma, chronic ulcerative colitis) and in 96 individuals with gastric, colonic or rectal carcinoma and to compare these levels with the values of a control group of 130 healthy individuals. We have found that the frequency of average values of analyzed micronutrients in precancerous groups was decreasing in the order vit C > vit E/vit A > Se > beta-car. The average levels of vitamins and beta-carotene were significantly reduced in all carcinoma groups, while selenium level showed a decrease only in the gastric carcinoma group. Copper level was elevated in the ulcerative colitis group and in all groups with carcinoma. The results indicate a frequent insufficient saturation of organism by natural antioxidants in groups with precancerous lesions and carcinomas of stomach and colorectum. Therefore, it is necessary to increase the general consumption of fruits and vegetables in Slovakia as a part of primary prevention of malignant diseases in these organs. Chemoprevention may be recommended in individuals with precancerous lesions.

Key words: Gastric and colorectal precancerous lesions, gastric and colorectal cancer, antioxidant vitamins, selenium, zinc, copper.
NEOPLASMA, 47, 1, 2000, 37-40


Do de novo acute myeloid leukemias with normal cytogenetics involve two main prognostic categories distinguished by the presence of erythroblastic and/or megakaryocytic dysplasia?

P. Lemež, J. Gáliková, T. Haas

Department of Hematology and Blood Transfusion, Hospital Jihlava, 586 00 Jihlava;
Institute of Hematology and Blood Transfusion, Prague;
Insitute of Biophysics, 1st Medical Faculty, Charles University, Prague, Czech Republic

De novo acute myeloid leukemias (AML) patients with normal cytogenetics represent a standard risk cytogenetic group. Erythroblastic and/or megakaryocytic dysplasia (EMD) in diagnostic bone marrow smears of 28 consecutive AML patients with a normal karyotype was studied. Twelve patients 21–85 (median 48) years old were categorized without EMD, 14 patients 34–90 (median 58) years old with EMD, and 2 patients were not evaluable for EMD. One cycle of induction therapy 4 + 7, with 4 doses of daunorubicin 45 mg/m2/d and standard doses of cytosine arabinoside for 7 days induced 10 complete and 2 partial remissions in 12 cases without EMD but lead to only one complete remission, 6 non-responses and 3 induction deaths in 10 cases with EMD (p = 0.002). However, high doses of cytosine arabinoside plus daunorubicin induced complete remission in 6 of 7 patients with EMD. In patients under 66 years treated by intensive consolidations the estimate of median survival was 50.6 months in 10 cases without EMD, significantly higher than 8.0 months in 11 cases with EMD (p = 0.043). De novo AML with normal cytogenetics might be divided into two biological categories, the first favorable-risk category without EMD and the second poor-risk category with EMD.

Key words: De novo acute myeloid leukemia, normal karyotype, erythroblastic dysplasia, megakaryocytic dysplasia, remission induction, survival.
NEOPLASMA, 47, 1, 2000, 41-47


Chromosomal changes in somatic cells in seminoma patients after treatment with ionizing radiation or cytostatics

C. Bilban-Jakopin

Department of Radiation Oncology, Institute of Oncology, SI 1000 Ljubljana, Slovenia; e-mail: tina.bilban@siol.net

Seminomas are sensitive to both ionizing radiation and cytostatic drugs. The study’s objective was to find out the effects of cytostatics or ionizing radiation by comparing the results of genome testing before treatment and immediately afterwards. Repeat cytogenetic testing six months after completion of treatment was used to find out changes resulting from reparatory processes after various types of treatment and the degree of elimination of defective lymphocytes from circulation.
Three cytogenetic tests were used in our study to find out structural changes in chromosomes (percentage of aberrations), sister chromatid exchanges (SCE) and the number of micronuclei in binuclear lymphocytes (MN).
In patients treated with ionizing radiation, strong inhibition of the mitotic activity of lymphocytes occurred after irradiation of para-aortal and ipsilateral inguinal lymph nodes. However, it is difficult to make a connection between the mitotic activity of lymphocytes and their total number, which was found to be within a normal range throughout the study. There is, therefore, another possibility, i.e. that this process actually involves impairment of intracellular enzymes and blockage of the synthesis of macromolecules in lymphocytes which have suffered a large degree of genome damage.
Six months after a completed course of irradiation, mitotic activity was found to be mostly normal; however, there was still a very high percentage of aberrations compared with group II (patients treated with a cytostatic, paraplatin) or with respect to the control group, in which the average percentage of aberrations was 1.42 (excluding dicentrics and rings, which are found in all irradiated patients).
From the cytological-mutagenetic point of view, chemotherapy proved to be less aggressive to patients. The results of recovery were visible earlier and the elimination of damaged cells was quicker.

Key words: Testicular tumor, cytogenetic test, chromosoma aberration, radiotherapy, chemotherapy.
NEOPLASMA, 47, 1, 2000, 48-55


HDR intraluminal brachytherapy in the treatment of malignant bronchial obstructions

J. Petera, R. Neumanová, M. Vrba, P. Čoupek, F. Salajka, A. Hrazdírová, M. Kučera, T. Snížek, P. Kolman, V. Hanák

Department of Radiotherapy, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic;
University Maternity Hospital, Brno, Czech Republic;
Clinic of Chest Diseases, University Hospital Bohunice, Brno, Czech Republic;
Department of Chest Diseases, Břeclav, Czech Republic;
Department of Chest Diseases, Jihlava, Czech Republic;
Department of Chest Diseases, Kyjov, Czech Republic;
Department of Chest Diseases, Třebíč, Czech Republic

Symptomatology of malignant intrabronchial obstructions has a serious negative effect on the quality of patients’ life. Intrabronchial brachytherapy can play an important role in the palliation of these symptoms.
Between December 1996 and September 1998 48 patients suffering from malignant intrabronchial obstructions were treated with intraluminal brachytherapy in the Dept. of Radiation Oncology at the University Maternity Hospital in Brno. Gammamed HDR automatical afterloading equipment was used to treat all patients.
The first group (23 patients) was treated with a combination of intraluminal brachytherapy and external radiotherapy. The second group (18 patients who had relapsed after previous external radiotherapy) was given intraluminal radiotherapy only. A third group (7 patients) underwent intraluminal brachytherapy only.
In the first group 17 patients (77%) showed symptomatic relief with tumor regression on X-ray in 16 patients and with bronchoscopic regression in 19 patients. Seven patients died before October 1998 having survived 1–6 months after the first brachytherapy application. Sixteen patients are still alive (1–14 months).
In the second group, 10 patients (56%) reported significant improvement of symptoms, with endoscopic regression in 12 patients. Twelve patients died before October 1998 surviving 1–6 months after the first brachytherapy session, 6 patients are still alive 1–5 months after the first brachytherapy fraction.
In the third group, bronchoscopy confirmed a complete disappearance of intrabronchial lesion in two cases with early intrabronchial tumor. Five patients reported symptomatic improvement with endoscopic regression of the tumor.
There was only one complication recorded: bronchospasm in one patient. The short follow up and limited number of patients does not allow comment on the late effects and survival, yet.
In conclusion, intraluminal brachytherapy is an effective and safe approach for palliation of malignant bronchial obstructions.

Key words: Intrabronchial malignant obstructions, intraluminal HDR brachytherapy, palliative effect.
NEOPLASMA, 47, 1, 2000, 56-59


Synergistic cell killing by combination therapy of retinoic acid and hyperthermia in human epidermoid laryngeal carcinoma cells in culture

P. Mukherjee, K. Banerjee, S.K. Das

Unit of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Calcutta-700 026, India

In vitro monolayer culture and clonogenic assay were used to investigate the individual and combined effect of temperature and retinoic acid (RA) on cellular morphology and colony forming ability of human epidermoid laryngeal carcinoma (HEp-2) cells. 20 micromol. RA alone inhibited multilayer formation and induced cell flattening. Hyperthermia (42°C) individually caused formation of cytoplasmic processes and irregularities in cellular shape and size. Combined effect of hyperthermia (42°C) and 20 micromol. RA treatment caused bleb formation on cell surfaces and lysis of cytoplasmic and nuclear membrane. RA treatment also caused dose-dependent reduction of colony growth. Heat-induced cell killing was only observed at lethal temperatures of 43°C and above. RA in combination with heat synergistically inhibited colony formation even at non lethal temperatures of 41 and 42°C. These results indicate that RA in combination with hyperthermia may facilitate the therapy of human epidermoid larynx carcinoma.

Key words: Retinoic acid, hyperthermia, epidermoid carcinoma, cell killing.
NEOPLASMA, 47, 1, 2000, 60-67


Recent trends in cancer mortality in the Slovak Republic and in Europe

E. Ginter

Institute of Preventive and Clinical Medicine, 833 01 Bratislava, Slovak Republic; e-mail: ginter@upkm.sk

During the last 30 years the trends in cancer mortality in Europe significantly changed. In 1970 the male and female cancer mortality (all ages) was higher in the Western Europe than in the ”socialist” Central and Eastern Europe. After 1970 in most Western countries decrease or no change of male premature (0–64 years) cancer mortality was observed. The decrease was deepest in Finland and in United Kingdom. In the most of the former communist countries an increase of both total and premature male cancer mortality was observed, especially in Hungary, Poland, Roumania, Bulgaria and in some regions of the former Soviet Union. Present male premature cancer mortality in Hungary is two-times higher than the average of European Union. Male cancer mortality in the Slovak Republic is at least two-times higher than in United Kingdom, Switzerland or Sweden. These differences are partially explainable by the higher prevalence of smoking in the East. The further risk factor could be oxidative stress, caused by low intake of antioxidants and high intake of spirits. In female populations, the differences between East and West are not so dramatic, with the exception of extremely high mortality in Hungarian females. Paralel increase of female lung cancer mortality both in the West and East is caused probably by the continually increasing smoking prevalence in females almost in the whole Europe. Further local risk factors in Eastern Europe (e.g. pollution) need to be identified with more specificity for preventive programs in Eastern Europe. This region is a prospective area for the research on lesser known cancer risk factors, e.g., chronic deficiency of antioxidants, natural anticarcinogens and psychosocial disorders.

Key words: Cancer, premature mortality, males, females, Slovak Republic, Europe.
NEOPLASMA, 47, 1, 2000, 68-72