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1.
Inflamm Res ; 64(3-4): 193-203, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25672799

ABSTRACT

OBJECTIVE: It was tested as to why low-dose methotrexate (MTX) effective against rheumatoid arthritis poses considerable health risk at higher doses. METHODS: The tumorigenic potential of My1/De blast cells was followed by cytology and by the kinetics of (18)FDG uptake. The toxicity of MTX on chromatin condensation was compared to predictive normal intermediates of chromosome condensation in control cells. RESULTS: MTX below 0.1 µg/ml did not cause visible changes in interphase chromatin structure. At its lowest toxic concentration (0.1 µg/ml) chromatin margination was confined to the outer edge of the nucleus. Between 0.1 and 5 µg/ml concentrations apoptotic chromatin shrinkage correlated with the dose of MTX. Apoptosis was exerted in early S phase excluding the mitotic effect. At higher MTX concentrations (>10 µg/ml) necrotic disruption and expansion took place. The lowest necrotic concentration (10 µg/ml) was close to highest apoptotic MTX concentration (5 µg/ml). CONCLUSIONS: The switch from apoptosis to inflammatory necrosis taking place within a narrow concentration range supports the notion of a narrow therapeutic spectrum. Chromatin changes are early markers of genotoxicity at much lower concentrations than citogenetic changes in properly chosen sensitive cells.


Subject(s)
Antimetabolites, Antineoplastic/pharmacology , Apoptosis/drug effects , Chromatin/drug effects , Leukemia, Myeloid/pathology , Methotrexate/pharmacology , 9,10-Dimethyl-1,2-benzanthracene/adverse effects , Animals , Bone Marrow Cells/drug effects , Bone Marrow Cells/pathology , Cell Cycle/drug effects , Cells, Cultured , Chromatin/chemistry , Chromatin/pathology , DNA Packaging/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Leukemia, Myeloid/chemically induced , Male , Rats , Rats, Long-Evans
2.
J Cancer ; 5(7): 548-58, 2014.
Article in English | MEDLINE | ID: mdl-25057306

ABSTRACT

UNLABELLED: The aim of this study is to select among potential tumor models that could be suitable to follow the metastatic spead of tumor cells. (18)FDG-PET tumor diagnostic test has been adapted to investigate tumor growth in vivo in local and metastatic rat models. Materials and Methods. The expression of glucose transporters was traced by immunohistological analysis, followed by the uptake of (18)FDG and visualized by MiniPET scanner. After s.c. administration of hepatocarcinoma (He/De) cells intensive local tumor growth and (18)FDG uptake were measured. RESULTS: Whole body (18)FDG-PET imaging supported by histological analysis have shown that subcutaneously growing tumors did not project metastases to other sites from the injected area. To avoid local tumor formation i.v. injection was chosen, but did not improve the safety of tumor cell administration. Tumor formation after i.v. injection took a longer time than after s.c. administration. Tumors upon i.v. generation were smaller and detectable in liver and lung, but not in other organs or tissues. iii) Subrenally implanted He/De cells spread from the retroperitoneal primary tumor of the kidney to thoracal paratymic lymph nodes (PTNs). The spread from primary site to metastatic tumors in PTNs was confirmed by post mortem surgery and histological examinations. CONCLUSION: Among the three methods applied: a) Local s.c. administration of tumor cells generated local tumors unsuitable to study metastasis. b) Intravenous administration causing unpredicatable location of tumor formation is not regarded a reliable metastatic tumor model. c) Subreanal implantation model proved to be a suitable model to follow the metastatic process in rats.

3.
DNA Cell Biol ; 31(4): 470-8, 2012 Apr.
Article in English | MEDLINE | ID: mdl-21942442

ABSTRACT

The distinguishable morphologic features of nuclei of acute myelogenous leukemia cells with enlarged size and finely distributed nuclear chromatin indicate incomplete chromosome condensation that can be related to elevated gene expression. To confirm this, interphase chromosome structures were studied in exponentially growing rat myelomonocytic leukemia 1 cells isolated at the University of Debrecen (My1/De cells). This cell line was established from primary rat leukemia chemically induced by 7,12-dimethylbenz[a]anthracene treatment. The enlarged nuclei of My1/De cells allowed improved fluorescent visualization of chromosomal structures. Increased resolution revealed major interphase intermediates consisting of (1) veil-like chromatin, (2) chromatin ribbon, (3) chromatin funnel, (4) chromatin bodies, (5) elongated prechromosomes, (6) seal-ring, spiral shaped, and circular chromosomal subunits, (7) elongated, bent, u- and v-shaped prechromosomes, and (8) metaphase chromosomes. Results confirmed the existence of the chromatin funnel, the first visible interphase chromosome generated by the supercoiling of the chromatin ribbon. Other intermediates not seen previously included the spiral subunits that are involved in the chromonemic folding of metaphase chromosomes. The existence of spiral subunits favors the helical coil model of chromosome condensation. Incomplete chromatin condensation in leukemia cells throughout the cell cycle is an indication of euchromatization contributing to enhanced gene expression and is regarded as a leukemic factor.


Subject(s)
Chromatin Assembly and Disassembly/physiology , Chromosomes, Mammalian/ultrastructure , Gene Expression Regulation, Neoplastic/physiology , Interphase/physiology , Leukemia, Myeloid/physiopathology , 9,10-Dimethyl-1,2-benzanthracene , Animals , Cell Line, Tumor , Female , Indoles , Microscopy, Fluorescence , Models, Biological , Rats , Rats, Long-Evans
4.
Histol Histopathol ; 25(3): 309-20, 2010 03.
Article in English | MEDLINE | ID: mdl-20054803

ABSTRACT

The aim of the study was to determine the tumorigenic potential of two cell lines established from N-nitrosodimethylamine induced rat hepatocarcinoma (HeDe) and mesenchymal renal tumors (NeDe). The basis of the distinction is that human cancers are known to overexpress facilitative GLUT transporters and TGF-beta1 protein. These proteins are linked to the increased metabolic energy consumption indicating uncontrolled growth and proliferation. We have assayed not only the expression of GLUT-1, GLUT-3 and TGF-beta1 proteins, but also the uptake of 2-fluoro-[18F]-2-deoxy-D-glucose (18FDG), a tracer for cancer diagnosis. Western blot analysis and whole body autoradiography were used to measure the 18FDG uptake of tumor cells. Elevated 18FDG uptake was measured in both tumor cell lines. Whole body autoradiography provided evidence that the uptake of 18FDG was lower in the necrotic inner part than in the more vascularized outer parts of primary hepatocarcinoma and mesenchymal renal tumors. GLUT-1 overexpression in hepatocarcinoma tumor, and high levels of GLUT-3 were found in the NeDe cell line and in the mesenchymal renal tumor. TGF-beta-1 was overexpressed in hepatocarcinoma and mesenchymal renal tumors. In vitro and in vivo parameters support the view that the tumorigenic potential of cancer cells cannot be determined by the expression of a single parameter such as the expression of either GLUT-1, GLUT-3 or 18FDG uptake. Besides the tumorigenic potential of the hepatocarcinoma, the high metabolic activity of the renal tumor indicated by its 18FDG uptake, GLUT-3 and TGF-beta1 expression, the mesenchymal renal tumor induced by N-nitroso-dimethylamine is not a benign, but an an aggressive renal carcinoma.


Subject(s)
Carcinoma, Hepatocellular/chemically induced , Dimethylnitrosamine/toxicity , Kidney Neoplasms/chemically induced , Liver Neoplasms/chemically induced , Mesenchymoma/chemically induced , Analysis of Variance , Animals , Autoradiography , Biomarkers, Tumor/metabolism , Blotting, Western , Carcinogenicity Tests , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/metabolism , Cell Cycle/physiology , Cell Line, Tumor , Flow Cytometry , Fluorodeoxyglucose F18/metabolism , Glucose Transporter Type 1/metabolism , Glucose Transporter Type 3/metabolism , Immunohistochemistry , Kidney/diagnostic imaging , Kidney/metabolism , Kidney Neoplasms/diagnostic imaging , Kidney Neoplasms/metabolism , Liver/diagnostic imaging , Liver/metabolism , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/metabolism , Mesenchymoma/diagnostic imaging , Mesenchymoma/metabolism , Microscopy, Fluorescence , Radionuclide Imaging , Rats , Transforming Growth Factor beta1/metabolism
5.
Anticancer Res ; 29(6): 2121-6, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19528472

ABSTRACT

BACKGROUND: The ultimate cause of cancer death is, in most cases, the appearance of metastases. The aim of the present study was to contribute to animal experimental investigations of metastatic tumor development. MATERIALS AND METHODS: Rat hepatocarcinoma (He/De), mesoblastic nephroma (Ne/De) cells, and in other cases tumor-bearing lymph nodes were transplanted under the renal capsule of F344 rats. Metastatic potential of tumor cells was examined by whole body autoradiography and phosphor image analysis. The organ distribution of cells was also investigated. RESULTS: Transplanted tumor cells resulted in metastases in the parathymic lymph nodes. Implanted India ink also demonstrated connection between the lymphatic vessels of the renal capsule and the parathymic lymph nodes. The metastatic potential was independent of the primary tumor growth rate. CONCLUSION: The renal capsule-parathymic lymph node complex seems to be suitable for the isolated in vivo examination of metastatic development and for the detailed analysis of secondary tumors.


Subject(s)
Carcinoma, Renal Cell/secondary , Disease Models, Animal , Kidney Neoplasms/secondary , Liver Neoplasms/pathology , Lymph Nodes/pathology , Thymus Gland/pathology , Wilms Tumor/secondary , Animals , Carcinoma, Renal Cell/pathology , Female , Kidney Neoplasms/pathology , Lymphatic Metastasis , Male , Rats , Rats, Inbred F344 , Subrenal Capsule Assay , Tumor Cells, Cultured , Wilms Tumor/pathology
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