Electronic Library of Scientific Literature


Volume 44 / No. 5 / 1997

Experimental chemotherapy of murine melanomas: Is there a discrepancy compared to clinical experience?

J. Borovanský

2nd Department of Medical Chemistry and Biochemistry, 1st Faculty of Medicine, Charles University, 128 53 Prague 2, Czech Republic

There has been a discrepancy between promising results of experimental chemotherapy in animal melanoma models and clinical response rates. This inconsistency seems to reflect weak points of the assays used so far to monitor the response of melanoma cells to chemotherapeutic agents. Therefore a less usual approach was chosen in the present study: Tumor cells were cultured in peritoneal cavity (B16 melanoma in inbred C57BL/6J mice and Cloudman S91 melanoma in inbred DBA2 mice) to maintain normal in vivo conditions; the animals were receiving the tested agents in i.p. injections and the prolongation of their life span was considered as the principle parameter of therapeutic efficiency of the compounds tested. Previously described therapeutic potency both of vitamins (C, alpha-tocopherol acid succinate) and some phenols (hydroquinone, 4-hydroxyanisole) was not confirmed. Benzoate, spin trap N-butyl-alpha-phenyl-nitrone and ammonium chloride as a lysosomotropic agent failed to increase the survival of melanoma-bearing mice. Free radical scavenger methimazole exerted a therapeutic effect in mice with pigmented B16 melanoma. Only classic cytostatic agents - cisplatin and cyclophosphamide - proved its therapeutic effect in both melanoma models studied. These results are in accord with the known resistance of human melanoma to conventional chemotherapy. Measurement of serum activity of gamma-glutamyltransferase was shown to be useful for monitoring therapeutic effect.

Key words: Melanoma, gamma glutamyltransferase, chemotherapy.
pp. 277-281

DNA ploidy in malignant melanoma, skin cancer and pigmented nevi

J. Skowronek, K. Adamska, K. Filipiak, Z. Karaś, R.M. Krenz, R. Rutkowski, J.B. Warchol

Great Poland Cancer Center, Department of Radiotherapy, 61-866 Poznań, Poland;
Department of Radiobiology and Cell Biology, University of Medical Sciences, Poznań, Poland;
Department of Tumor Pathology, University of Medical Sciences, Poznań, Poland;
Department of Immunology and Clinical Allergology, University of Medical Sciences, Poznań, Poland

The determination of DNA content in human cancers is the subject of increasing interest, particularly in view of its potential clinical applications. There are relatively few studies which describe DNA content of skin neoplasms and pigmented nevi. These studies have shown conflicting results.
In the present investigation the authors measured DNA ploidy using flow and video-imaging cytometry in 51 malignant melanomas, 20 skin cancers and 48 pigmented nevi. For DNA measurement paraffin embedded tissues and fresh cell smears were used. Clinical and histological data of malignant melanomas were recorded and correlated with DNA ploidy. DNA histograms were examined for DNA aneuploidy by DNA Index. DNA ploidy in primary lesions of melanomas and their metastases were compared.
The aneuploidy rate, found in our observation, was significantly higher in whole malignant melanoma group, in clinical Stage II and III, in tumors with thickness greater then 1.5 mm, tumors with Clark level III,IV and V. Another clinical and histological factors did not show significant correlation with ploidy. Aneuploidy was found in 8 of 20 (45.0%) skin cancers. In the whole population of pigmented nevi aneuploid DNA content was identified in 10 nevi (20.1%).
The results of this study suggest that aneuploidy seems to be connected with advanced stage of malignant melanoma but it does not replace other prognostic factors. Both cytometric methods can be used for routine DNA ploidy analysis. Ploidy studies are not useful for predicting metastatic potential of primary melanoma. Results obtained from fresh cell smears and paraffin embedded tissues were identical.

Key words : Malignant melanoma, skin cancer, pigmented nevi, DNA ploidy, flow cytometry, video-imaging cytometry.
pp. 282-288

A cell surface antigen that cross-reacts with My4, a monoclonal antibody to CD14, is expressed on human monoblastic cell line U937, B-lymphoma cells, and polymorphonuclear leukocytes

T. Ikemoto, T. Nakagawa, M. Hatanaka, M. Hasegawa, T. Kageyama, M. Hirano, A. Shimizu

Central Clinical Laboratory, Osaka Medical College, Takatsuki 569, Japan;
Department of Clinical Pathology, Osaka Medical College, Takatsuki, Japan;
Second Department of Medicine, Osaka Medical College, Takatsuki, Japan;
Department of Medicine, Fujita Health University, School of Medicine, Toyoake, Japan

The CD14 antigen was originally identified on monocytes as a differentiation marker and usually detected by a panel of monoclonal antibodies, including My4 and LeuM3. Recent studies have shown that CD14 antigen is expressed on Langerhans cells, a subset of normal B-lymphocytes, neutrophils, and subtypes of B-cell non-Hodgkin's lymphomas. These antigens, however, react with My4, but not with LeuM3, and the reason for this has not been elucidated. In this study, we found that similar My4+/LeuM3- epitopes are expressed on the human monoblastic cell line, U937. Northern blotting demonstrated that the U937 cells express neither 1.4 kb CD14 transcripts nor possible alternative spliced forms of CD14 transcripts. The molecule was resistant to phosphatidylinositol specific phospholipase C, which effectively hydrolyzes glycosyl-phosphatidylinositol anchored protein, decay accelerating factor, on the same cells. Lipopolysaccharide, which down-regulates the expression of CD14 on monocytes, did not alter the expression of the molecule. We concluded that the My4+/LeuM3- molecule on U937 cells is not CD14 antigen but another surface protein. A similar molecule was also detected on B-lymphoma cells from a patient with non-Hodgkin's lymphoma and on polymorphonuclear leukocytes from healthy donors.

Key words: My4-cross reactivity, PI-PLC-resistant, mRNA, LPS stimulation, lymphoma.
pp. 289-294

Tumor angiogenesis in pulmonary adenocarcinomas: Relationship with basic fibroblast growth factor, its receptor, and survival

I. Takanami, F. Tanaka, T. Hashizume, S. Kodaira

First Department of Surgery, Teikyo University School od Medicine, Tokyo 173, Japan;
Department of Pathology, Teikyo University School of Medicine, Tokyo, Japan;
Department of Surgery, National Sanatorium, Kanagawa Hospital, Hatano, Kanagawa, Japan

Tumor angiogenesis was examined in tissue specimens from 120 patients with a pulmonary adenocarcinoma. The microvascular density (MVD) was determined by the factor 8-related antigen (F8RA), and the basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor 1 (FGFR1) protein expressions were immunologically studied with the MVD. Patients with over 30 counts of the MVD showed significantly poorer prognosis than those with less than 30 counts. bFGF and FGFR1 expressions correlated with tumor angiogenesis and prognosis. Univariate analysis showed that the MVD, bFGF, and FGFR1 had a significant effect on prognosis, and multivariate analysis of three prognostic factors revealed the MVD correlated with survival.
Our findings suggest that bFGF and FGFR1 expressions play an important role in tumor angiogenesis and that the bFGF and FGFR1 expressions promote angiogenesis and metastasis in pulmonary adenocarcinoma, and that the MVD is a useful prognostic marker for assessing the outcome of a pulmonary adenocarcinoma.

Key words: Tumor angiogenesis, basic fibroblast growth factor, fibroblast growth factor receptor 1, pulmonary adenocarcinoma, prognostic indicator, immunostaining.
pp. 295-298

Prognostic factors in astrocytomas: Relationship of p53, MDM-2, BCL-2 and PCNA immunohistochemical expression to tumor grade and overall patient survival

J. Ehrmann, Jr., Z. Kolář, B. Vojtěšek, M. Kala, S. Komenda, A. Oulton

Centre of Molecular Biology and Medicine, Laboratory of Molecular Pathology, Palacký University, 775 15 Olomouc, Czech Republic;
Masaryk Memorial Hospital, Brno, Czech Republic;
Clinic of Neurosurgery, School of Medicine, Palacký University, Olomouc, Czech Republic;
Institute of Biometry, School of Medicine, Palacký University, Olomouc, Czech Republic;
Centre of Molecular Biology and Medicine, Laboratory of Molecular Pathology, Palacký University, Olomouc, Czech Republic

The immunohistochemically detected expression of p53, BCL-2, MDM-2 and PCNA proteins in samples of tumor tissues of 42 patients with astrocytomas or glioblastoma multiforme was statistically compared to degree of malignancy and overall survival. We found relation between p53 protein expression and survival in the high grade astrocytomas group (more cases of p53 immunonegative tumors with longer survival), and significantly higher BCL-2 protein expression as well as significantly higher MDM-2 protein expression in the group of low grade astrocytomas. PCNA protein expression showed any relation to tumor grade or survival. Despite the rather small number of samples these results support the hypothesis that MDM-2 protein may be a potent regulator of functional p53, expressed in low grade astrocytoma only.

Key words: Astrocytoma, p53, BCL-2, MDM-2, survival, proliferative activity.
pp. 299-304

Does the concentration of alpha1-proteinase inhibitor reflect the transformation of liver cirrhosis to liver carcinoma?

M. Dabrowska, M. Mantur, A. Panasiuk, J. Prokopowicz

Institute of Laboratory Diagnostics, 15-276 Bialystok, Poland;
Department of Infectious Diseases, University Medical School, Bialystok, Poland

Serum concentration of alpha1-proteinase inhibitor (alpha1-PI) was determined by nephelometric method in forty seven patients with liver cirrhosis (LC) and fifteen patients with hepatocellular carcinoma (HCC).
Our data show an increase in the concentration of alpha1-PI in the group with decompensated LC by 17% and in HCC by 29%. The level of alpha1-PI higher than (220 mg%) may be indicative of the disease progression towards decompensated LC or HCC.
In the conclusion, an increase in alpha1-PI concentration in patients with LC may be considered as an alarming factor, but is not sufficiently specific to become a diagnostic tool for the detection of HCC development.

Key words: alpha1-proteinase inhibitor, liver cirrhosis, hepatocellular carcinoma.
pp. 305-307

Androgen level variations, clinical response to LHRH agonists and changes in the quality of life subscales in metastatic prostate cancer - speculations about possible role of the monoamine system

I. Popov, S. Jelić, D. Radosavljević, Z. Nikolić-Tomašević

Institute of Oncology and Radiology of Serbia, 11 000 Belgrade, Yugoslavia

The aim of this study was to investigate the effect of goserelin-acetat (Zoladex®) on testosterone suppression, to compare achieved suppression with clinical effects in patients with prostate cancer with bone metastases and consequent painful syndrome, to study the behavior of adiol during treatment and to assess life quality with emphases on the physical and psychological domain in relation to clinical and biological treatment effects. Fifteen patients were treated by Zoladex® in one dose every 28 days, and followed-up for 12 months. All patients had several metastatic localizations in the bones, initial high prostate specific antigen (PSA), and high acid (AP) and alkaline phosphatase (ALP). PSA, testosterone, adiol (delta-5-androstenediol), luteinizing hormone (LH), foliculostimulating hormone (FSH), ALP and AP were also measured before every cycle. For evaluation of the life quality Rotterdam Symptom Checklist was used.
Clinical progression was not registered during follow-up, with drop of PSA, ALP and AP. Testosterone and adiol displayed mainly inverse trends during treatment. The complete testosterone suppression was never achieved. It seems that Zoladex® has quite different influence on LH and FSH, as levels of those hormones have shown opposite trend. Some of the observed hormonal effects could be attributed to stimulation of the monoamine system. Suppression of LH level provoked by administration of LHRH agonists increases level of dopamine in hypothalamus which inhibits releasing of its hormones. By inhibition of corticotropic releasing factor and ACTH, and by its influence on adrenal gland, we could explain drop of adiol levels in the first months of administration of LHRH agonists. Testosterone increase and adiol drop in the first months, and adiol increase following testosterone level drop in the fourth to eight month, may be explained by negative feed back mechanism between different androgens which could be stimulated or provoked by LHRH therapy. The question of effects which are results of LHRH agonists modulation of the monoamine system and consequent activation of other central mechanisms of hormonal regulation is still open. Patients' quality of life under therapy was improved for about 30% in psychological and functional domains. There were no significant changes on physical subscale, during treatment. It seems that the obtained positive psychological treatment effect is not only a consequence of pain decrease, but it could be the result of the change in the level of monoamines in CNS under Zoladex®.

Key words: Monoamines, testosterone, goserelin, prostatic neoplasms, quality of life.
pp. 308-313

Bacteremia in neutropenic versus nonneutropenic cancer patients: Etiology and outcome in 401 episodes

M. Mrázová-Studená, L. Drgoňa, S. Špánik, 1 I. Krúpová, M. Baláž, P. Pichna, P. Koreň, J. Šufliarsky, J. Mardiak, A. Kunová, J. Trupl, V. Krčméry Jr.

Department of Medicine, University of Trnava, Slovakia;
Department of Chemotherapy, Postgradual Medical School, Bratislava, Slovakia;
Department of Chemotherapy, Department of Microbiology, National Cancer Institute, Bratislava, Slovakia;
St. Elisabeth Cancer Institute, Bratislava, Slovakia

Etiology, risk factors, symptomatology and outcome of 401 bacteremic episodes during the period of 6 years in a National Cancer Institute occurring among 9987 admissions were analyzed.
Neutropenia as an independent risk factor was observed in 198 episodes, while 203 bacteremic episodes appeared in nonneutropenic patients. Both groups were compared in risk factors, etiology, clinical symptomatology and outcome.
Proportion of particular pathogens did not show significant differences in both groups, except for E. faecalis occurring more frequently in the group of nonneutropenic patients in contrast to Enterobacteriaceae, occurring more frequently in neutropenic patients. There was significant by higher proportion of anaerobic bacteremia and fungemia in neutropenic than in nonneutropenic patients. Prior prophylaxis with quinolones with breakthrough bacteremia were also seen more frequently in the group of neutropenic patients. Septic shock and death due to bacteremia occurred more frequently in the group of neutropenic patients.

Key words: Neutropenia, bacteremia.
pp. 314-318

Effect of tumor cells on the activation of murine lymphocytes and macrophages by cisplatin and FK565

A. Kumar, S.M. Singh, A. Sodhi

Cellular Immunology Laboratory, Department of Zoology, University of Delhi, Delhi, India;
Immunology Laboratory, School of Biotechnology, Banaras Hindu University, Varanasi-221005, U.P. India

Murine peritoneal macrophages on in vitro treatment with cisplatin (5 µg/ml) or FK565 (10 µg/ml) showed an enhanced production of tumor necrosis factor (TNF) and reactive nitrogen intermediates (RNI). Similarly, treatment of splenic lymphocytes with these agents also led to an enhanced production of TNF. Co-incubation of macrophages or splenic lymphocytes with P815 (a murine mastocytoma) cells in vitro in the absence of cisplatin or FK565 also resulted in an augmented TNF production, however, it had no effect on the RNI production by macrophages. TNF production of cisplatin- or FK565-treated macrophages got synergistically enhanced in the presence of P815 cells whereas the production of RNI was inhibited. Incubation of splenic lymphocytes with P815 cells in the presence of cisplatin or FK565 resulted in an inhibition of TNF production. Indomethacin-treated P815 cells were observed to be less effective in inhibiting nitrite production of macrophages compared to untreated tumor cells. Pretreatment of P815 cells with cisplatin or FK565 before co-incubation did not alter the TNF production of macrophages whereas it inhibited the same in lymphocytes. This study shows that activation of macrophages and lymphocytes is independently influenced by P815 tumor cells in combination with chemoimmunotherapeutic drugs cisplatin and FK565.

Key words: Macrophages, splenic lymphocytes, P815 cells, tumor necrosis factor, reactive nitrogen intermediates.
pp. 319-323

Glutathione S-transferase activity as an early marker for malignant tumors of corpus uteri

M. Osmak, D. Babić, M. Abramić, A. Ambriović, D. Miličić, D. Eljuga, L. Vuković

Department of Molecular Genetics, Ruđer Bošković Institute, 10 000 Zagreb, Croatia;
Department of Gynecology and Perinatal Pathology, Medical School, University of Zagreb, Zagreb, Croatia;
Department of Chemistry, Ruđer Bošković Institute, Zagreb, Croatia;
Department of Obstetrics and Gynecology, Medical School, University of Zagreb, Zagreb, Croatia;
Department of Gynecology, University Hospital for Tumors, Zagreb, Croatia

Glutathione (GSH) concentrations and glutathione S-transferase (GST) activities were determined in 30 paired malignant human corpus uteri tumor samples and in samples of adjacent normal tissues. For GSH concentrations no difference was found between normal (126.0 ± 52.4 nmol/mg protein) and tumor tissues (110.1 ± 46.4 nmol/mg protein; p = 0.219). The GST activities were significantly higher in tumor tissues (322.4 ± 135.54 nmol/min/mg protein) than in corresponding normal tissues (224.6 ± 95.64 nmol/min/mg protein; p = 0.005). This activities were independent on the pathohistological and clinical factors, except for positive lymphovascular invasion and myometrial invasion (over 50%), where significantly lower GST activities were found. For normal tissues the positive correlation between GSH concentrations and GST activities was found (correlation coefficient = 0.50, p = 0.005), but not for tumor tissue (correlation coefficient = 0.20, p = 0.281). The prognosis of patients (according to the well established prognostic factors, such as tumor type, myometrial invasion and grades) who had lower GSH concentration and GST activity in normal tissue was similar to those with higher GSH concentration and GST activity. In conclusion, higher GST activities found in tumor of corpus uteri suggest, that GST activity could be used as a tumor marker for the early stages of these malignant tumors.

Key words: Glutathione, glutathione transferase, tumors of corpus uteri, tumor marker.
pp. 324-328

Inhibition of experimental murine tumors by MT81, a new mycotoxin from Penicillium nigricans

M. Gupta, U.K. Majumdar, M.R. Ray, D.K. Mukhopadhayay

Department of Pharmacological Technology, Jadavpur University, Calcutta - 700032, India;
Chittaranjan National Cancer Research Centre, Calcutta, India

Effects of a new mycotoxin MT81 obtained from the fungal strain Penicillium nigricans on the growth of two transplantable murine tumors and the life span of the hosts were studied. Remarkable decrease in tumor volume and viable tumor cell count was found in both the tumors. Antitumor effect of the compound was more pronounced in Sarcoma 180 (S180) than in Ehrlich ascites carcinoma (EAC). The tumor - inhibitory effect was also manifested by the reduction in mitotic activity and appearence of membrane blebbing and intracytoplasmic vacuoles in the treated tumor cells. MT81 treatment prolonged the life span of the EAC tumor host by 78% and more than 100% in S180 bearing mice. Tumor inhibition by MT81 was followed by improvements in hemoglobin, RBC values and bone marrow cellularity. Thus the results suggest that MT81 has significant antitumor property against experimental murine tumors and it does not adversely affect the hematological profile of the hosts.

Key words: MT81, new mycotoxin, tumor inhibition, mice.
pp. 329-333


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