Electronic Library of Scientific Literature


Volume 47 / No. 4 / 2000




The role of chemotherapy in prostate cancer - Minireview

K. Odrážka, J. Vaňásek, M. Vaculíková, J. Stejskal, S. Filip

Department of Oncology and Radiotherapy, Charles University Hospital, 500 05 Hradec Králové, Czech Republic, e-mail: odrazka@fnhk.cz;
Department of Radiotherapy, Regional Hospital, Pardubice, Czech Republic;
Department of Radiotherapy, Regional Hospital, Jihlava, Czech Republic

Hormonal therapy in disseminated prostate cancer is effective in 70-80% of patients and prolongs their lives of a mean 1-2 years. Sooner or later, androgen independence develops due to a multifactorial mechanism. A smaller part of patients may respond to second-line hormonal manipulations (antiandrogen withdrawal, adrenal enzymes synthesis inhibitors, corticosteroids).
In hormone-refractory disease only about 30% of patients would respond to chemotherapy. In the standard chemotherapy the mostly used cytotoxic agents are anthracyclines, platinum derivatives, vinca alkaloids and cyclophosphamide. However, combined chemotherapy is not more effective than monotherapy. Conventional chemotherapy may improve especially the quality of life. The median survival in chemotherapy patients (6-12 months) is not significantly longer when compared with the best supportive care.
In recent years the main concern has been focused on new cytotoxic drugs and different combinations with hormonal agents. In Phase II studies the combinations of estramustine with oral etoposide, estramustine with taxanes and alternating weekly regimens (doxorubicin, ketoconazole/estramustine, vinblastine) show higher response rates (53-69% of patients with prostate-specific antigen decline of more than 50%) and longer survival (13-19 months) than conventional chemotherapy.

Key words: Prostate cancer, hormone-refractory, chemotherapy.
Neoplasma, 47, 4, 2000, 197-203


Retrovirus vector containing wild type p53 gene and its effect on human glioma cells

J. Hlavatý, S. Tyukosová, J. Bies, K. Hlubinová, Č. Altaner

Cancer Research Institute, Slovak Academy of Sciences, 833 91 Bratislava, Slovak Republic, e-mail: exonalt@savba.sk

A retroviral vector containing wild-type p53 tumor suppressor gene (wt-p53) under the control of viral LTR sequences was constructed and transfected into packaging cell line GP+envAm12. Virus producing single cell clone GP+envAm12/p53clC8 (8 x 105 cfu/ml, determined on NIH 3T3 cells) was isolated and used to transfer wt-p53 gene into human glioma cell lines in vitro. Decreased viability in p53-infected cells as compared to uninfected or empty virus infected cells was observed.

Key words: p53 gene, retrovirus vector, gene therapy.
Neoplasma, 47, 4, 2000, 204-211


Constitutive ubiquitination and degradation of c-Myb by the 26S proteasome during proliferation and differentiation of myeloid cells

S. Feiková, L. Wolff, J. Bies

Laboratory of Molecular Virology, Cancer Research Institute, Slovak Academy of Sciences, 833 92 Bratislava, Slovak Republic, e-mail: exonbies@savba.savba.sk;
Laboratory of Cellular Oncology, National Cancer Institute, NIH, Bethesda, USA

Steady state levels of transcription factors play an important role in proliferation and differentiation of hematopoietic cells. The transcription factor c-Myb is frequently activated by retrovirus integration in murine and avian leukemias. Its deregulation has been also implicated in human acute and chronic leukemias and some other nonhematopoietic tumors. It is a short-lived protein, which is rapidly degraded by the 26S proteasome. Truncation at the carboxyl (COOH) terminus, which has occurred in some oncogenic forms of c-Myb, results in the increased resistance to proteolysis. This stabilization correlates in vitro with less efficient ubiquitination. Here, we report the first evidence of post-translational modification of c-Myb by ubiquitin in vivo using HA-labeled ubiquitin. We also show that, in contrast to the unstable wild type or amino (NH2)-terminally truncated c-Myb form, stable carboxyl (COOH)-terminally truncated c-Myb is not targeted to degradation by covalent attachment of ubiquitin in vivo. In addition, following an analysis of subcellular fractionation of proteins from cells treated with a 26S proteasome inhibitor we were able to localize c-Myb exclusively in the nuclear compartment, suggesting the absence of a requirement for export to cytoplasm prior proteolytic processing. Furthermore, pulse-chase experiments of c-Myb protein isolated from interphase cells or cells synchronized in the G2/M or G1 phases of cell cycle did not reveal substantial cell cycle dependent differences in proteolytic processing by the 26S proteasome. Also, the demonstration that the half-life of c-Myb in myeloid progenitor M1 cells induced to differentiate along the monocytic pathway is the same as in undifferentiated cells suggested that proteolytic breakdown of c-Myb is a constitutive process during proliferation and differentiation.

Key words: c-Myb, proteolysis, 26S proteasome, ubiquitin, cell cycle.
Neoplasma, 47, 4, 2000, 212-218


Approaches to identification of HNPCC suspected patients in Slovak population

I. Fridrichová, D. Ilenčíková, W. Friedl, P. Hlavčák, M.Škorvaga, P. Križan, J. Pálaj, M. Piršel, E. Farkašová, Z. Bartošová

Cancer Research Institute, Slovak Academy of Sciences, 833 91 Bratislava, Slovak Republic, e-mail: exonfri@savba.sk;
National Cancer Institute, Bratislava, Slovak Republic;
Institute for Human Genetics, University of Bonn, Bonn, FRG;
Hospital of Bojnice, Bojnice, Slovak Republic

Patients with hereditary non-polyposis colorectal cancer (HNPCC) have a DNA mismatch repair defect (MMR) in their tumor tissue that results in instability of microsatellite DNA sequences (MSI). Thus, MSI analysis may effectively indicate this form of cancer that should be then proved by analysis of germline mutations in MMR genes. The aim of this study was to identify HNPCC suspected patients in the Slovak population by investigating microsatellite instability in colorectal tumor tissues. MSI was studied at 5-11 loci in matched tumor and normal DNA using radioactively labeled PCR products separated on sequencing gels. High microsatellite instability (MSI-H) was present only in patients younger than 50 years, in 100% of patients having two affected relatives by colorectal cancer and in 67% of patients with only one affected relative. In both groups of patients colorectal cancer was present in two successive generations. No MSI-H was found in the group of patients older than 50 years, even if they had positive family history for colorectal cancer. Among all markers used, the BAT26 mononucleotide repeat (100%), D10S197 and D13S175 (62.5%) dinucleotide repeats were the most frequently altered in the tumor tissues. Retrospective analysis revealed that some of the patients having MSI-H tumors have had clinicopathological characteristics frequently reported to HNPCC. The family members of those patients with MSI-H are enrolled in preventive health care program until mutational analyses will enable to select carriers from non-carriers of mutated MMR genes.

Key words: Microsatellite instability, hereditary non-polyposis colorectal cancer, DNA mismatch repair, genotype-phenotype correlation.
Neoplasma, 47, 4, 2000, 219-226


Mammary carcinogenesis induced in Wistar:Han rats by the combination of ionizing radiation and dimethylbenz(a)anthracene: prevention with melatonin

K. Môciková, M. Mníchová, P. Kubatka, B. Bojková, I. Ahlers, E. Ahlersová

Institute of Animal Physiology, Faculty of Science, P.J.Šafárik University, 04167 Košice, Slovak Republic, e-mail: iahlers@kosice.upjs.sk

The primary cancer chemoprevention is an important topic of experimental oncology. We have analyzed the possible oncostatic properties of melatonin in a combined model of radiation plus chemocarcinogen-induced mammary carcinogenesis. Virgin female rats of Wistar:Han strain were continuously irradiated with daily dose 96 mGy of gamma rays up to 15 days. At the end of irradiation, between 52-60 postnatal days, 7,12-dimethylbenz(a)anthracene was administered by gavage, in three 10 mg/rat consecutive doses. A part of animals drank melatonin in a concentration 100 microg/ml of tap water, continuously from the beginning of irradiation and 26 weeks after its end. The aim of the experiment was to investigate the preventive effect of melatonin on mammary tumor patterns. Relatively low incidence of mammary tumors in the noninfluenced group was probably connected with generally very low sensitivity of Wistar:Han female rats to single dose of chemocarcinogen in mammary carcinogenesis induction. In our trial melatonin decreased markedly the volume of mammary tumors, but did not influence any other tumor characteristics.
The chemopreventive effect of melatonin, derived from in vivo realized mammary carcinogenesis study in female Wistar:Han rats was limited. The cancer preventive properties of melatonin should be investigated in the future especially from the standpoint of susceptible strain, effective doses, and mode plus sufficient length of application.

Key words: Irradiation plus chemocarcinogen, rats, chemoprevention, melatonin.
Neoplasma, 47, 4, 2000, 227-229


Repeated administration of carcinogen in critical developmental periods increases susceptibility of female Wistar: Han rats to mammary carcinogenesis induction

B. Bojková, I. Ahlers, P. Kubatka, K. Môciková, M. Mníchová, E. Ahlersová

Institute of Animal Physiology, Department of Science, P. J. Šafárik University, 041 67, Košice, Slovak Republic, e-mail: iahlers@kosice.upjs.sk

Analysis and knowledge of individual strain susceptibility of experimental animals to induction of carcinogenesis is important especially in regard to possibility of transfer of these facts to human pathology, first of all to chemopreventive projects. Our group (Ahlers et al. [1]) reported very low sensitivity of female Wistar:Han rats to induction of mammary carcinogenesis by 7,12-dimethylbenz(a)anthracene (DMBA) and by N-methyl-N-nitrosourea (NMU). The aim of this paper was to increase the sensitivity of females of this strain to mammary carcinogenesis induction by repeated administration of NMU in a dose 50 mg/kg of b.w. in critical periods: on 3-4 postnatal days, on 21 day (critical period for development of ductal parts of mammary gland) and between 50-55 days (maximal proliferation of whole gland). In comparison with 38% incidence of mammary tumors after the single dose and 65% incidence after 3 subsequent doses between 50-60 days, the combination of administration (only) on 21 day and between 50-55 postanatal days resulted in 88% incidence - the sensitivity of animals reached the level of highly susceptible rat strains. The latency period was significantly increased in groups with NMU given on 3-4, 21 days and between 45-55 days respectively, on 21 day and between 45-55 days in comparison with control group (one dose of NMU). The tumor frequency per group and per animal in all groups with repeated NMU administration was significantly higher than that of control group. The volume of tumors was not influenced either by repeated carcinogen application or by time of its administration.
These results expand the possibilities of analysis of carcinogen effects in individual periods of rat postnatal development.

Key words: Rat strain, sensitivity, chemocarcinogens, critical periods.
Neoplasma, 47, 4, 2000, 230-233


Chromosomal aberrations, sister chromatid exchanges and high frequency cells in young patients with neurofibromatosis 1 (NF1)

M.P. Bigatti, G. Ardito, L. Lamberti, S. Crovella, M. Collell, S. Giordanino, L. Benso

Department of Animal and Human Biology, Torino University, 10123 Torino, Italy, e-mail: bigattip @ dba.unito.it;
Institute of Antropology, Firenze University, Firenze, Italy;
Chair of Genetics, School of Medicine, Trieste University, Trieste, Italy;
Center of Auxology, Department of Science for Children and Adolescents, Torino University, Torino, Italy

Chromosomal aberrations (CAs), sister chromatid exchanges (SCEs) and high frequency cells (HFCs) have been assessed in peripheral blood lymphocytes of 10 neurofibromatosis (NF1) patients and 10 healthy controls.
In both groups, the spontaneous rates and the induced (bleomycin for CA and MMC for SCE) frequencies were analyzed. No differences between cells from NF1 patients and controls were observed with respect to spontaneous or bleomycin induced CA. Spontaneous or MMC induced SCE frequencies were also similar in NF1 patients and controls. HFCs, on the contrary, were statistically lower in NF1 patients.

Key words: NF1, chromosomal aberrations, SCE, HFCs, bleomycin, mytomycin C.
Neoplasma, 47, 4, 2000, 234-238


Sequential intermediate high-dose therapy with etoposide, ifosfamide and cisplatin for patients with germ cell tumors

J. Mardiak, P. Fuchsberger, J. Lakota, T. Šálek, Z. Syčová-Milá, M.Drahokoupilová, M. Baláž, I.Koza

Department of Medicine, National Cancer Institute, 833 10 Bratislava, Slovak Republic, e-mail: mardiak.jozef@ba.telecom.sk

Intermediate high dose VIP (etoposide, ifosfamide, cisplatin) achieved comparable efficacy and improved tolerance in comparison with high-dose chemotherapy plus PBSC in poor risk germ cell tumors. The aim of this study was to confirm the effectivity and tolerance of this regimen in clinical practice.
Twenty-five consecutive patients, 9 previously untreated with poor prognosis and 16 relapsed, were treated with 1.6 VIP or 1.9 VIP+PBSC. A relative dose intensity of 1.6 VIP was used in 14 patients and 11 patients received the intensity of 1.9 VIP.
Clinical response was achieved in 56% of patients. Fifty-eight percent of patients have survived more than 1 year and 44% more than 2 years. No significant difference was noted between previously treated and untreated patients, as well as between the patients on 1.6 VIP and 1.9 VIP, with the exception of improved 1-year survival of patients on 1.9 VIP. One of four cisplatin-refractory patients achieved durable partial remission with a normal level of tumor markers. Serious non-hematological toxicity was rare. Myelotoxicity of 1.9 VIP was less serious in comparison with 1.6 VIP regimen, but the difference was not significant.
Sequential intermediate high-dose therapy is an effective and tolerable regimen for patients with poor risk germ cell tumor as well as for relapsed patients.

Key words: 1st line, high dose chemotherapy, NSGCT, salvage.
Neoplasma, 47, 4, 2000, 239-243


Carboplatin and cyclophosphamide in the treatment of metastatic seminoma

J. Mardiak, T.Šálek, Z. Syčova-Milá, J. Šufliarsky, M. Baláž, I. Koza

Department of Medicine, National Cancer Institute, 833 10 Bratislava, Slovak Republic, e-mail: mardiak.jozef@ba.telecom.sk

Cisplatin-based chemotherapy is highly effective in advanced seminoma, but at the cost of a  considerable toxicity. The response rate of carboplatin is comparable with cisplatin combinations but the relapse rate is higher. Our study assesses the efficacy and the toxicity of the combination of carboplatin and cyclophosphamide in patients with advanced seminoma.
Nineteen consecutive patients received 6 cycles of intravenous cyclophosphamide 750 mg/m2 and carboplatin 350 mg/m2, repeated every 21 days. The overall objective response rate was 100%, 11 patients (58%) achieved a complete response and 8 patients (42%) showed a partial response. At median follow up of 4.2 years 3 patients (15%) relapsed. The 2-year disease-free survival and the overall survival are 72 and 94%, respectively. This outpatient treatment was well tolerated and the toxicity was mild. One patient had granulocytopenic fever and one patient had grade 3 cystitis. The combination therapy with carboplatin and cyclophosphamide is an effective and tolerable regimen in advanced seminoma.

Key words: Germ cells tumor, advanced seminoma, carboplatin, cyclophosphamide, chemotherapy.
Neoplasma, 47, 4, 2000, 244-247


Double modulation of 5-fluorouracil by leucovorin and low-dose methotrexate in advanced colorectal cancer

B. Štabuc, A. Markovič, A. Plesničar, T.E. Cizej

Department of Medical Oncology, Institute of Oncology, 1000 Ljubljana, Slovenia, e-mail: borut.stabuc@kclj.si

A phase II study was carried out to evaluate the efficacy and toxicity of a double biochemical modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and leucovorin (LV) in patients with advanced unresectable colorectal cancer. Forty-two patients with measurable metastases of colorectal cancer were treated with 5-FU in daily doses of 600 mg/m2 given in a 6-hour intravenous (i.v.) infusion on days 1-5, LV 50 mg/m2 i.v. on days 2,3 and 5, and MTX 40 mg/m2 i.v. on days 1 and 4, every 4 weeks. Twenty-eight patients had a single metastatic site, eleven double, whereas three had more than two metastatic sites. Objective response (one complete response) was observed in 12 of 40 patients (30%) (95% confidence interval 16-48), stable disease in 19 patients (47%) and progression in 9 patients (23%). Overall median survival was 12 months. Median time to progression was 6 months. Treatment was generally well tolerated. The most frequent adverse reactions were stomatitis (38%), nausea and vomiting (35%), diarrhea (31%), leukopenia (18%), and plantar-palmar erythroderma (15%). The combination of 5-FU, LV and MTX seems to be an active regimen in advanced colorectal cancer.

Key words: Colorectal cancer, 5-fluorouracil, methotrexate, biochemical modulation.
Neoplasma, 47, 4, 2000, 248-252


Long-term (15 years) results of extended field radiotherapy in Hodgkin’s disease

Ľ. Ševčíková, E. Bolješíková, M. Chorváth, G. Kovačičová

Slovak Postgraduate Academy of Medicine, 833 03 Bratislava, Slovak Republic, e-mail: lsevciko@ouse.sk;
St. Elisabeth Cancer Institute, 812 50 Bratislava, Slovak Republic

From 1975 to 1990, 214 patients with the pathological Stage IA, IB, IIA, IIB and IIIA of Hodkgin‘s disease were treated by supradiaphragmatic and/or infradiaphragmatic mantle technique. Complete remission was achieved in 70 patients (8%) by means of radiotherapy on1y. Partial remission was achieved in 9 patients (2%). The survival at 10 years was 86% and 15 years it was 66%. The most frequent late complications were hypothyreosis, Lhermitte‘s syndrome and radiation pneumonitis.

Key words: Hodgkin’s disease, extended field radiotherapy, overall survival, disease-free survival, complications.
Neoplasma, 47, 4, 2000, 253-256


Clinical stages of cutaneous malignant melanoma in Bulgaria

P. Troyanova, Z. Valerianova, S. Danon

National Oncological Center, 1756 Sofia, Bulgaria, e-mail: popov@mgmu.bg

The aim of the study was to investigate the distribution of the newly diagnosed cases with cutaneous malignant melanoma by clinical stages in Bulgaria over the period 1993-1995 as a reason for improving both melanoma prevention and control.
Over the period 827 new cases with cutaneous malignant melanoma are registered in the country. A representative sample of 671 cases has been taken.
The cases with a localized melanoma (Stage I and II) were prevalent - 509 (75.8% of all studied cases). The thick melanomas (Stage IIB) were most frequently encountered among the primary lesions. They were 207 cases (30.8%). The thin melanomas (Stage IA) were only 41 (6.1%). The proportion of the cases with nodal and in-transit metastases (Stage III) - 122 (18.2%) and the proportion of the cases with distant metastases (Stage IV) - 40 (6.0%) were quite high.
The analysis of the results shows that the cases with cutaneous malignant melanoma in Bulgaria are detected quite late. The cases with early-diagnosed melanoma are prevalent among women, young persons and urban population, and the cases with advanced melanoma are more frequent among men, persons older than 50 and rural population.

Key words: Cutaneous malignant melanoma, clinical stages, diagnosis.
Neoplasma, 47, 4, 2000, 257-260