Electronic Library of Scientific Literature


Volume 46 / No. 3 / 1999


Renal cell carcinoma - associated immune impairment that may interfere with the response to cytokine therapy

L. Lauerová, L. Dušek, M. Šimíčková, F. Rovný, V. Spurný, A. Rovný, P. Šlampa, J. Žaloudík, A. Rejthar, J. Wotke, J. Kovařík

Department of Cellular and Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic;
RECETOX Faculty of Natural Sciences, Masaryk University, Brno, Czech Republic;
St. Ann?s University Hospital, Brno, Czech Republic;
University Hospital, Bohunice, Brno, Czech Republic

This prospective study was carried out to explore cytokine-related immune alterations in 69 renal cell carcinoma patients (RCC) and to look for changes which might potentially serve as a reliable predictors of response to cytokine-based therapy. Interleukin-2 (IL-2), its soluble receptor (sIL-2R) and tumor necrosis factor (TNF-alpha) levels produced in vitro by PHA activated and intact mononuclear cells (PBMC) were determined. Concentrations of IL-2, IL-4, IL-6, sIL-2R, TNF-alpha and CRP were measured in sera. Cytokine level was evaluated by enzyme-linked immunoadsorbent assay (ELISA) and CRP was determined by means of turbidimetric method. All measurements were performed in patients without any prior treatment.
PHA activated PBMC of RCC patients were significantly defective in producing IL-2 and TNF-alpha comparing to controls (p < 0.03 and p < 0.001). The difference of sIL-2R was noted in metastatic stage only (p < 0.03). Unstimulated PBMC manifested decrease in IL-2 (p < 0.03) and increased level of TNF-alpha in advanced disease (p < 0.02). This impairment reflected tumor size and differentiation stage. Serum concentrations of IL-2, sIL-2R and TNF-alpha were within normal range. However, in relation to the clinical stage, significantly increased serum IL-2 was noted in combined Stage I and II as compared to controls (p = 0.012). IL-6 and CRP showed markedly elevated levels with a significancy which allowed to distinguish samples from metastatic patients.
In conclusion careful comparisons of these data with clinical course of cytokine treated patients will disclose which of those tests may possess predictive power in the individual patients who are likely to respond to cytokine-based treatment.

Key words: Renal cell carcinoma, cytokine levels, abnormalities, prognostic and predictive value.
NEOPLASMA, 46, 3, 1999, pp. 141-149

p53 protein expression in resected invasive esophageal cancer

L. Chyczewski, M. Kozłowski, J. Nikliński, J. Szyszko, J. Laudański, W. Niklińska

Department of Pathological Anatomy, Medical Academy, 15-256 Bialystok, Poland;
Department of Thoracic Surgery, Medical Academy, Bialystok, Poland;
Department of Histology and Embryology, Medical Academy, Bialystok, Poland

Many studies have reported the increased expression of p53 protein in various human malignancies and its accumulation have been considered an intermediate biomarker in multistage carcinogenesis. This study was designed to evaluate p53 expression by immunohistochemistry using Dako p53, D0-7 monoclonal antibody in 33 resected invasive squamous cell esophageal cancers (SqCC). The relationship between p53 immunoreactivity and clinicopathologic parameters was determined by the Chi-square test and Student's t test. p53 protein overexpression (more then 10% positive staining cancer cells) was found in 15 out of 33 (45%) tumors. Positive test was found in 38% cases in Stage IIA, 57% in Stage IIB, 45% in Stage III and 50% cases in Stage IV. p53 overexpression was observed in 48% of tumors with lymph nodes metastases, and 41% of tumors without lymph nodes metastases. In respect of tumor differentiation, cases graded as G1, G2 and G3 were positive in 50%, 50% and 40%, respectively. Thirteen per cent of patients with p53 protein overexpression and 16% of patients without p53 protein overexpression survived more than 3 years. There was no correlation between p53 overexpression and stage, tumor differentiation, lymph nodes metastases, and patients survival.
In conclusion our results showed that p53 overexpression did not correlate with clinicopathologic feature of invasive SqCC of the esophagus and p53 protein overexpression was unsuitable for predicting the outcome of patients after surgical resection.

Key words: Invasive esophageal cancer, p53 protein, immunohistochemistry.
NEOPLASMA, 46, 3, 1999, pp. 150-155

Potential carcinogenicity of the synthetic 1,3,6-triazine (6-azapyrimidine) nucleic acid analogues determined by DC polarography. II. Nucleosides of 6-azauracil

L. Novotný, A. Vachálková, A. Pískala

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Kuwait;
Cancer Research Institute, Slovak Academy of Sciences, 833 91 Bratislava, Slovak Republic;
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 6, Czech Republic

The polarographic reduction of six synthetic 1,3,6-triazine (6-aza) nucleosides with 6-azauracil as the nucleoside base in the strictly anhydrous solutions was studied in the absence and presence of alpha-lipoic acid. The values of the half-wave potentials E1/2 and the parameter of potential carcinogenicity tg alpha were compared for six nucleosides of 6-azauracil and two nucleosides of 4-thio-6-azauracil. The current value of the first diffuse polarographic wave or a new diffuse polarographic wave belonging to the nucleoside-alpha-lipoic acid complex increased with the increase of the alpha-lipoic acid concentration for the all compounds only marginally. Although this diffuse current increase was linear and dependent on the alpha-lipoic acid concentration in anhydrous solutions, the determined index tg alpha values ranged between 0.027 and 0.114. This is an indication of a very low potential carcinogenicity of the all nucleoside analogues investigated.

Key words: 1,2,5-triazine nucleosides, 6-azauracil, 6-azauridin, reduction potentials, carcinogenicity, DC polarography, parameter tg alpha.
NEOPLASMA, 46, 3, 1999, pp. 156-160

Transformation kinetics of the 5'-chloro-5'-deoxy analogue of arabinosylcytosine

M. Stankovičová, L. Novotný, M. Bachratá, J. Bílková, P. Rauko

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovak Republic;
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Safat, Kuwait;
Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovak Republic

5'-Chloro-5'-deoxy arabinosylcytosine (Cl-araC) is a more lipophilic analog of the clinically used drug - arabinosylcytosine (araC). The resistance toward the enzyme cytidine-deaminase action was described as an characteristic feature of this synthetic nucleoside. The kinetics of the Cl-araC transformation in acid and alkaline solutions was studied at various temperatures. When compared with parent compound araC, the chlorine atom at the 5' position of the nucleoside sugar moiety increases the Cl-araC stability. The chlorine atom stabilizing effect is higher in acidic conditions. Cl-araC increased stability, antileukemic activity accompanied by higher lipophilicity confirm the fact that Cl-araC belong among interesting compounds from the point of view of cancer chemotherapy.

Key words: 2',5'-anhydro-arabinosyluracil, 5'-chloro-5'-deoxyarabinosylcytosine, transformation kinetics of nucleoside analog, stability.
NEOPLASMA, 46, 3, 1999, pp. 161-165

The increase of the rate of hemopoietic recovery and clinical benefit of the erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) with peripheral blood progenitor cells (PBPC) after intensive cyclic chemotherapy in high-risk breast cancer patients

S. Filip, J. Vaňásek, M. Bláha, P. Měřička, J. Vávrová, K. Podzimek

Department of Oncology and Radiotherapy, Charles University Hospital, 500 05 Hradec Králové, Czech Republic;
Department of Clinical Hematology, Charles University Hospital, Hradec Králové, Czech Republic;
Department of Tissue Bank, Charles University Hospital, Czech Republic;
Military Medical Academy JEP, Hradec Králové, Czech Republic

The role of erythropoietin (EPO) plus granulocyte-colony stimulating factor (G-CSF) combination in hemopoietic recovery was studied in patients with high-risk breast carcinoma and compared to a control group of previously treated identical patients who were not given EPO plus G-CSF.
Eleven consecutive patients admitted to this study had Stage III or IV breast cancer. They received 6 cycles of intensive chemotherapy (epirubicin 150 mg/m2 and cyclophosphamide 1300 mg/m2). The 1st cycle served for mobilization of peripheral blood progenitor cells (PBPC). At its end leukaphereses collections of PBPC were performed to be used as hematologic support (PBPCT) in the 5 remaining cycles. The administration of EPO plus G-CSF was started when leukocyte (WBC) count in peripheral blood dropped below 1 x 109/l and hemoglobin (Hb) level fell below 100 g/l. The treatment was stopped when leukocyte count rose to 5 x 109/l and Hb to 130 g/l.
EPO plus G-CSF combination after PBPCT produced significant effects in terms of hemopoietic recovery, clinical benefit and supportive care requirements when compared with 12 historic control patients: Periods of leukopenia were shorter which resulted in reduced risk of infectious complications. The grades of leukopenia in the study and control groups were as follows: grade 4 (36 vs. 18%), grade 3 (57 vs. 30%), grade 2 (7 vs. 13%) respectively. Significantly shorter was the time of PLT recovery < 50 x 109/l (p < 0.001). The grades of thrombocytopenia were: grade 4 (29 vs. 11%), grade 3 (21 vs. 12%), grade 2 (25 vs. 36%) respectively.
The number of necessary transfusions was significantly reduced as well as the length of hospital stay (p < 0.001).
In conclusion, our results obtained in this study confirm that combination of EPO plus G-CSF not only increases the rate of hemopoietic recovery, reduces the number of necessary red blood cell and platelet transfusions but, at the same time, simplifies the clinical management and is more tolerable for the patients.

Key words: EPO and G-CSF, progenitor cells, CD34+ cells, PBPC, intensive chemotherapy, hemopoietic toxicity, hemopoietic recovery, breast carcinoma.
NEOPLASMA, 46, 3, 1999, pp. 166-172

Immunohistochemical analysis of HLA class II antigens and tumor infiltrating mononuclear cells in renal cell carcinoma: Correlation with clinical and histopathological data

D. Brašanac, J. Marković-Lipkovski, J. Hadži-Djokić, G.A. Müller, C.A. Müller

Institute of Pathology, School of Medicine, University of Belgrade, 11 000 Belgrade, Yugoslavia;
Institute of Urology and Nephrology, Clinical Centre of Serbia, Belgrade, Yugoslavia;
Centre of Internal Medicine, Department of Nephrology and Rheumatology, Georg August University, Göttingen, FRG;
Medical University Clinic, Section of Transplantation Immunology and Immunohematology, Eberhard-Karls University, Tübingen, FRG

Cryostat sections of 37 renal cell carcinomas (RCC) - 25 clear cell type, 10 granular and 2 chromophobe - were studied with indirect immunoperoxidase method applying monoclonal antibodies (MoAb) to HLA-DR, -DP and -DQ antigens for analysis of HLA class II antigens, and anti-CD14, -CD3, -CD4 and -CD8 MoAb for tumor infiltrating mononuclear cells (TIM). Number of positive cells was estimated semiquantitatively and results of immunohistochemical investigation were correlated with clinical (patient age and sex, tumor size and TNM stage) and histopathological (cytology, histology, grade) characteristics of RCC. All RCC expressed HLA-DR, 92% -DQ and 73% -DP antigens with level of expression in hierarchy -DR>-DQ>-DP, but no statistically important correlation could be established with any of the histopathological or clinical parameters analyzed. Monocytes were more abundant than T lymphocytes and CD4+ than CD8+ T cells, whereas tumors with T lymphocyte predominance and approximately equal number of CD4+ and CD8+ T cells had greatest average diameter. Inadequate activation of T lymphocytes by tumor cells (despite capability of antigen presentation) could be the reason for association of parameters which indicates more aggressive tumor behavior with aberrant HLA class II antigen expression on RCC.

Key words: HLA class II antigens, renal cell carcinoma, immunohistochemistry, tumor infiltrating mononuclear cells.
NEOPLASMA, 46, 3, 1999, pp. 173-178

Changes after conservative surgical treatment for early breast carcinoma: Comparison of sonographic and bioptic findings

J. Slobodníková

Department of Radiology, St. Elisabeth Cancer Institute, 812 50 Bratislava, Slovak Republic

The aim of the study was evaluation of interventional ultrasound in the diagnostics of changes after conservative surgical treatment for early breast carcinoma and in the therapeutic removal of postoperative seromas. The analysis of USG- and bioptic findings in 240 breast cancer patients after conservative breast surgery performed between 1996-1998 is reported. The major findings were: postoperative scars, granulomas, seromas, hematomas, fat necrosis, skin thickening, inflammatory changes and local tumor recurrence. In our experience, the interventional ultrasound coupled with cytological examination are reliable methods for the follow up of early and late postoperative changes with sufficient degree of correlation between USG- and histologic findings.

Key words: Invasive ultrasonography, breast cancer, postoperative changes, conservative surgery, histologic and cytologic findings.
NEOPLASMA, 46, 3, 1999, pp. 179-181

Sole brachytherapy of the tumor bed after breast conserving surgery: A new radiotherapeutic strategy for patients at low risk of local relapse

C. Polgár, T. Major, A. Somogyi, J. Fodor, J. Tóth, Z. Sulyok, G. Forrai, Z. Takácsi-Nagy, L.C. Mangel, G. Németh

Department of Radiotherapy, National Institute of Oncology, H-1122, Budapest, Hungary;
Centre of Experimental and Human Tumorpathology, National Institute of Oncology, Budapest, Hungary;
Department of Surgery, National Institute of Oncology, Budapest, Hungary;
Department of Radiology, Haynal Imre University of Health Sciences, Budapest, Hungary

The aim of the study was to test the hypothesis, if there were subgroups of early breast cancer patients in which sole brachytherapy (BT) of the tumor bed was a feasible and safe treatment option after breast conserving surgery (BCS). Forty four prospectively selected patients with Stage I-II breast cancer were entered into a protocol of postoperative tumor bed irradiation using interstitial high dose rate (HDR) implants. The HDR fractionation schedules were calculated according to the linear quadratic model. In 8 patients 7 x 4.33 Gy, in the other 36 patients 7 x 5.2 Gy were delivered to the tumor bed with 2 cm margin. The treatment planning was based on the 3 dimensional (3D) reconstruction of the clipped excision cavity, catheters and skin points. A conformal semi-3D dose planning was used. The side effects were assessed by mammograms, MRI- and clinical examinations. At a median follow up of 20 (7-36) months 1 (2.3%) local and 1 (2.3%) regional failure was observed. Distant metastasis did not occure. The cosmetic results were judged to be excellent in each case. G2 radiation side effects were observed in 2 (4.5%) cases. Postoperative sole BT of the tumor bed with careful patient selection and adequate quality assurance seems to be a feasible alternative to whole breast radiotherapy after BCS. Sole BT shortens the time of radiotherapy from 5?6 weeks to 5 days, and reduces the costs of treatment. The skin and volume sparing effect of interstitial irradiation may decrease the side effects of radiotherapy. A randomized study is in progress to define which subgroups of patients should be candidates for BT alone after BCS.

Key words: Early invasive breast cancer, radiotherapy, sole brachytherapy, tumor bed, conformal treatment planning.
NEOPLASMA, 46, 3, 1999, pp. 182-189

Drug dose delivery and treatment outcome relationship in standard bleomycin, etoposide and cisplatin combination chemotherapy in nonseminomatous germ cell tumor patients

F. Gutierrez-Delgado, D.A. Titov, S.A. Tjulandin, A.M. Garin

Fred Hutchinson Cancer Research Center, 19024 Seattle, Washington, USA;
Cancer Research Center, Russian Academy Of Medical Sciences, Moscow, 115 478, Russian Federation

This study retrospectively evaluated the influence of drug dose delivery components (DDDC) of bleomycin, etoposide and cisplatin chemotherapy for metastatic nonseminomatous germ cell tumors on treatment outcome (NSGCT). Between December 1987 and January 1995, 75 NSGCT patients were treated with a median of 4 cycles (range 3-8) of cisplatin 120 mg/m2 on day 1, etoposide 100 mg/m2 on days 1 through 5 and bleomycin 30 U on days 1, 3, and 5 every 3 weeks. DDDC, such as cumulative dose, cumulative dose in mg/m2, dose intensity (DI), relative dose intensity (RDI), dose intensity products, and relative dose intensity products by drug, were calculated and tested as possible predictors of treatment outcome in patients classified according to Indiana University (IU), and International Germ Cell Cancer Cooperative Group (IGCCCG) classifications. Overall complete response (CR) rate was 64%, and 3-year progression-free survival (PFS) was 59%. By IU classification there were statistical differences in CR and survival between moderate (89-81%) and advanced disease (42-40%) (p < 0.005), while for patients classified according to IGCCCG criteria, statistical differences in CR and PFS there were not registered. DI (mg/m2/week) and RDI values for the entire group were: cisplatin 33-0.82; etoposide 133-0.80 and bleomycin 11-0.37. We did not observe a statistically significant difference in drug dose delivery components for treatment outcome between patients who achieved a CR and incomplete response when analyzed by either extent of disease or whole group. Extent of disease was the most important predictor of treatment outcome.

Key words: Germ cell tumors, testicular cancer, dose intensity, cisplatin, bleomycin, etoposide.
NEOPLASMA, 46, 3, 1999, pp. 190-195

Enhancement of radiosensitivity in human glioblastoma U138MG cells by tetrandrine

K.H. Chang, M.L. Chen, H.C. Chen, Y.W. Huang, T.Y. Wu, Y.J. Chen

Department of Radiation Oncology, Mackay Memorial Hospital, Taipli, 10449 Taiwan, Republic of China;
Department of Medical Research, Mackay Memorial Hospital, Taiwan, Republic of China;
Department of Chinese Martial Arts, Chinese Culture University, Taiwan, Republic of China

Tetrandrine, a natural lipid-soluble alkaloid with a low molecular weight, has both anti-tumor activity and a tissue-protective effect, as demonstrated in our previous studies. We studied tetrandrine to determine whether or not it enhanced radiosensitivity in human glioblastoma U138MG cells. Tetrandrine at concentration of 5.0 and 7.5 microg/ml dramatically enhanced the growth-inhibiting effect of radiation. This effect is dose-dependent on the dose of both tetrandrine and radiation. Moreover, we found that tetrandrine eliminated the cell cycle perturbation induced by radiation. Cells treated with tetrandrine alone as well as with a combination of tetrandrine and radiation became rounded, floated up and grew sparsely under observation under an inverted light microscope, DNA fragmentation was also noted by gel electrophoresis. These findings suggest that tetrandrine has potential as an adjunct to radiotherapy for glioblastoma.

Key words: Tetrandrine, radiosensitivity, U138MG.
NEOPLASMA, 46, 3, 1999, pp. 196-200