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PubMed1986

Fanconi's anemia. Clinical study of six cases.

Six cases of constitutional aplastic anemia (Fanconi's anemia), including four boys and two girls who were between 6 and 10 years of age, are presented. Congenital abnormalities were observed in all the patients, especially skin pigmentations, renal anomalies, and growth retardation. The initial symptoms were insidious, mainly related to the anemia. All patients were anemic and thrombocytopenic, but only three were leukopenic. Five cases showed increased levels of fetal hemoglobin, which was marked in two. Bone marrow obtained by aspiration and/or biopsy was hypocellular in all cases. Chromosomal studies showed breaks, ring- or cross-chromosomes, chromosome exchanges, and endoreduplications. Five cases were treated with androgens and a good response was obtained in all of them. Four patients died, and the remaining two are alive and well. The clinical and biological features of these patients are in accordance with those of previous reports. The importance of the androgen therapy is stressed; androgen dependence was observed in all cases.

Androgens↗
PubMed1985

Carbamoylation of glutathione reductase and changes in cellular and chromosome morphology in a rat cell line resistant to nitrogen mustards but collaterally sensitive to nitrosoureas.

A Walker 256 rat carcinoma cell line (WR) with acquired resistance to nitrogen mustards has been found to lack cross-resistance to nitrosoureas. Although total cellular glutathione pools were similar in the parent (WS) and resistant cell lines (WS, 2.5 X 10(-6); WR, 2.0 X 10(-6) mol/mg protein), glutathione reductase activity was 3.98 in WR compared to 8.67 nmol reduced nicotinamide adenine dinucleotide phosphate oxidized per microgram protein per min in WS cells. Treatment of cells with a carbamoylating nitrosourea, N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea, produced a dose-dependent inhibition of glutathione reductase and depletion of thiols in both cell lines. The drug caused no direct DNA strand breakage, but a differential mitotic spindle-chromosome stain showed that spindle formation was inhibited in WR cells at N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea concentrations of greater than 50 microM. In WS cells, mitotic figures were still visible at 100 microM. Chromosomal damage was expressed in both cell lines at concentrations of 25 microM. The number and extent of these aberrations were greater in WR than WS. Observed karyotypic abnormalities included polyploidy, chromosome decondensation, and endoreduplication. In interphase cells, transmission electron microscopy showed that the most prevalent drug-induced lesions included (a) disappearance of plasma membrane filopodia, (b) appearance of membrane blebbing, and (c) development of irregular crescent-shaped nuclei. These morphological and cytogenetic changes correlate with cytotoxic responses of these cell lines to N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea and would be consistent with drug-induced inhibition of glutathione reductase.

Animals↗
PubMed1985

Increased gene amplification in L5178Y mouse lymphoma cells with hydroxyurea-induced chromosomal aberrations.

Chromosomal aberrations and dihydrofolate reductase gene amplification are observed in L5178Y mouse lymphoma cells after treatment with hydroxyurea. The types of aberrations include polyploidy, endoreduplication, chromosome fragmentation, and the presence of extrachromosomal DNA. Hydroxyurea-treated cells analyzed by cell sorting showed a subpopulation of cells with increased DNA and increased dihydrofolate reductase. This subpopulation shows a high incidence of chromosome aberrations and an increased frequency of dihydrofolate reductase gene amplification. Hydroxyurea-treated cells with the normal amount of DNA and dihydrofolate reductase have few aberrations and a low frequency of dihydrofolate reductase gene amplification. We propose that hydroxyurea treatment causes overreplication of DNA and that recombination of overreplicated DNA can lead to chromosome aberrations and gene amplification.

Animals↗
PubMed1985

Endogenous blockage and delay of the chromosome cycle despite normal recruitment and growth phase explain poor proliferation and frequent edomitosis in Fanconi anemia cells.

BrdU-Hoechst flow cytometry was employed to study the proliferation kinetics of blood lymphocytes from patients with Fanconi anemia (FA). Compared to controls, untreated FA lymphocytes show normal response to PHA stimulation, normal G0/G1 exit rates, and normal first S-phase durations. The G2 phase of the first cell cycle, however, is severely prolonged, and 24% of the recruited population become arrested during the first chromosome cycle (S, G2/M phases). The delay suffered during G2 appears to be compensated in part by a subsequent G1 phase duration that is unusually short for postnatal human cells (3.7 +/- 0.5 hrs). In analogy to what has been observed in other cell systems after experimental delays of the chromosome cycle, we therefore postulate that at least some FA cells enter their second growth phase without prior completion of the delayed chromosome cycle. Renewed replication would ensue in such cells without prior passing through mitosis and cytokinesis, leading to endoreduplication, which is a frequent finding in the FA syndrome.

Adolescent↗
PubMed1983

[Tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) induces a protein in human lymphocytes binding satellite DNA].

Interactions between a satellite DNA fragment (SH3, 1.8 kb) cloned in pBR325 plasmid and DEAE-protein fractions from human lymphocytes treated with phorbol-12-myristate-13-acetate (TPA) have been studied by filtration technique through nitrocellulose filters. The 0.3 M fraction was found to have a protein which binds SH3 DNA specifically. Cytogenetic studies have shown an increased frequency of chromosome endoreduplications which may be due to the binding of TPA-induced protein to centromeres.

Bacteriophages↗
PubMed1984

Fluorescence cytophotometric analysis of megakaryocytic ploidy in culture: studies of normal and thrombocytopenic mice.

A system for the accurate and rapid measurement of the ploidy of cultured megakaryocytes derived from megakaryocytic colony-forming cells (CFU-M) has been developed. Thirty thousand murine marrow cells per milliliter were cultured for varying time periods in agar in the presence of horse serum and pokeweed mitogen-stimulated spleen cell-conditioned medium (PWM-SCM). To ensure the inclusion of all the megakaryocytic cells in the analysis, entire agar discs were transferred onto glass slides and dried. Cells of the megakaryocytic lineage were identified by staining for acetylcholinesterase (AchE) for two hours. Subsequently, the nuclei of the cells were stained using 1.7 X 10(-5) mol/L chromomycin A3, a specific DNA-binding fluorochrome. Megakaryocytic colonies (greater than or equal to 2 AchE+ cells) were located under transmission light. The fluorescence emission of each cell of the colony was then measured by a photometer interfaced with a computer. The mean fluorescence emission of about 20 random granulocytes per slide was used as a 2N standard. There was no significant cell loss, quenching of fluorescence by AchE staining, or overlapping of colonies or cells. Approximately 100 megakaryocytes per hour could be analyzed. Modal ploidy of cultured megakaryocytes increased from 2N to 32N between days 3 and 6 in culture. Varying concentrations of PWM-SCM from 5% to 20% did not affect the ploidy distribution when examined at day 5. The heterogeneity of the ploidy of cells within colonies increased continuously with increasing cell numbers per colony. Clonal analyses of mean ploidy and ploidy heterogeneity did not show distinct types or classes of colonies; rather, the data show that megakaryocytic colonies are structured as a continuum. An inverse correlation was found between the number of cells constituting the colonies and their mean DNA content. To determine if short-term in vivo exposure of CFU-M to a thrombocytopenic environment could affect the ploidy of their progeny, mice were given rabbit antimouse-platelet serum while control animals were given normal rabbit serum. Twenty-four hours after injection, marrow derived from these animals was cultured. At day 5, the ploidy distributions and ploidy heterogeneity were identical in both treated and control groups. Thus, factor(s) that promote CFU-M proliferation do not affect megakaryocytic endoreduplication, while stimuli that acutely influence megakaryocytic ploidy in vivo do not determine the ultimate ploidy potential of megakaryocytes derived from a CFU-M.

Acetylcholinesterase↗
PubMed1984

[Tumor cell kinetics in uterine cervical carcinoma following irradiation].

15 cases of squamous cell carcinoma of uterine cervix which received radiotherapy were investigated in order to elucidate tumor cell kinetics following irradiation. The DNA content of Pararosanillin-Feulgen stained tumor cells were measured by fluorescence cytophotometry which provided great precision in the field of microspectrophotometry. Besides the cell preparation, tumor cells were precisely identified under blue light excitation (405nm). It is of great value to obtain a reliable DNA histogram of tumor cells with this method. In both groups of radioresistant cases (n = 3) and radiosensitive cases (n = 12), the same trend in cell kinetics was noted until 1400 rad, such as G2-block, endoreduplication, and a decrease in the 2c cell (G0 + G1) population. Most of the residual cells at 3000 rad of radioresistant cases showed little irradiation-induced morphological change. These cells were proved to be 2C cells in this study. This indicates that these radioresistant cells were non-cycling cells (G0). The mean value for the 2C cell population before irradiation was 65% in radioresistant cases and 46% in radiosensitive cases, respectively. The former contained a larger proportion of 2C cells than the latter. Clinically, the 2C cell population before irradiation may be used as a useful parameter to forecast radiosensitivity.

Aged↗
PubMed1983

[Cytogenetic analysis of the Bloom syndrome. A study of the exchange-break relationship].

Cytogenetic study of a case of Bloom's syndrome (number 46 of the international registry) confirms the excess of exchanges in all cellular types with the exception of a minority of lymphocytes and of two lymphoblastoid cell lines. These exchanges are produced in an X or U fashion between sister chromatids or between homologous chromatids and produce both simple and complex figures for which symmetry is the common feature. Some of these structures are rearranged secondarily, producing centric or acentric fragments and marker chromosomes. Triradial configurations are considered to be the result of exchanges rather than of partial endoreduplication. Chromatid and chromosome breaks are interpreted to result from incomplete exchanges. It is suggested that the general propensity for exchanges is the primary event responsible directly or indirectly for the cytogenetic observations rather than a defect in one of the DNA-repair mechanisms. No increase in mitomycin C sensitivity appears in vitro. The excess of SCEs is partially correlated by contact in vitro with normal cells and to a lesser degree by the culture medium in which the cells were grown.

Adult↗
PubMed1982

Growth of human malignant micromegakaryocytes in vitro.

Mononuclear cells from the peripheral blood of a patient with megakaryoblastic transformation of Philadelphia chromosome-positive chronic myelogenous leukemia were cultured. Morphological and cytochemical studies and cell ploidy determinations were done daily for 4 days. PAS staining of the cells increased progressively during culture. Ultrastructural study of circulating and cultured cells revealed demarcation membranes and alpha granules indicating the cells were micromegakaryocytes. Deoxyribonucleic acid synthesis, determined by 3H-thymidine uptake, peaked at 72 hours. The DNA content of cultured cells was diploid at all times. All 15 metaphases analyzed at 72 hours were Ph1-positive. Malignant (Ph1-positive) megakaryoblasts and micromegakaryocytes grown successfully were capable of partial cytoplasmic maturation as demonstrated by glycogen deposition and increase in subcellular organelles, while endoreduplication was impaired. Malignant megakaryoblasts and micromegakaryocytes can be grown successfully in short term liquid culture and have more complete maturation in vitro than observed in vivo.

Cell Division↗
PubMed1981

[Cytogenetics in bone marrow transplantations. II. Acute lymphocytic leukemia].

In this we report cytogenetic data concerning two patients with Acute Lymphoblastic Leukemia (ALL), submitted to bone marrow transplantation. In one of two patients the chimere was present while in the other case it was absent, since the donor and the acceptor were of the same sex. However even in the latter case, the cytogenetic analysis was useful and led to the identification of endomitosis and endoreduplication phenomena, which are signs for an unlucky prognosis.

Bone Marrow Transplantation↗
PubMed1982

Centrioles and centrospheres in giant cells of human gliomas.

The ultrastructure and distribution of the centrioles and centrospheres in giant cells of three human gliomas were studied. In contrast with data on giant cells of other tumors, no enlarged centrospheres containing clusters of more than four centrioles could be found. Nor were any structural abnormalities of the centrioles encountered. In over 300 micrographs containing centrioles, the majority of the centrioles were solitary, a few formed diplosomes and rarely clusters of four. These findings do not support the view that giant tumor cells display anomalies in the structure or behaviour of the centrioles. Indeed, in these cells, as in normal non-giant cells, the clustering and distribution of the centrioles may reflect the status of the particular cell in the mitotic cycle. Our findings are consistent with the idea that giant cells may originate from several cycles of endoreduplication.

Cell Nucleus↗
PubMed1978

In vitro studies of mouse embryos bearing mutations in the T complex: t6.

Cultured blastocysts homozygous for the t6 mutation lose their inner cell mass within a few days of attachment to the culture dish. At about the same time it becomes apparent that putative t6-mutant trophoblast cells and their nuclei fail to enlarge to the degree of their normal counterparts. These abnormalities in mutant embryos are reflected by an abrupt drop on the seventh equivalent gestation day in the rate of increase of beta-glucuronidase activity. The failure of t6/t6 trophoblast nuclei to enlarge normally appears to be due partially to endoreduplication at a slower rate than normal trophoblast nuclei and partially to premature cessation of DNA synthesis. Analyses indicate that this abnormality is not reversed when mutant embryos are placed in chimeric association with normal ones. Trophoblast outgrowths from mutant and normal trophectodermal vesicles are similarly distinguishable by differences in outgrowth and nuclear size as well as DNA content and synthesis. Despite the fact that t6/t6 embryos and trophectodermal vesicles are phenotypically different from normals from early times in culture, the trophoblast cells in the mutant structures acquire and continue to produce two enzymes characteristic of trophoblast differentiation, delta 5, 3 beta-hydroxysteroid dehydrogenase and plasminogen activator. On the basis of these and previous observations, we propose that the primary effect of the t6 mutation is to cause a metabolic lesion which kills inner cell mass cells relatively quickly but which has a more gradual effect upon trophoblast cells. The fact that phenotypically recognizable t6/t6 trophoblast cells can survive for several days before dying makes this a potentially useful system in which to search for the t6 gene product(s).

Animals↗
PubMed1995

Cyclin D3 is essential for megakaryocytopoiesis.

A normal cell cycle in most eukaryotic cells consists of a tightly regulated sequence of phases including DNA synthesis (S) followed by a gap (G2), mitosis (M), and a gap (G1). In the megakaryocytic lineage, the cells undergo endomitosis, which involves DNA synthesis in the absence of mitosis, thus giving rise to polyploid cells. We aimed at defining whether the megakaryocytic cell cycle consists of a continuous S phase or of G1/S phases and at determining which cyclins are involved in this process. Studies were performed in primary cultures of mouse bone marrow cells. DNA synthesis in megakaryocytes was followed by determining incorporation of a DNA precursor, bromodeoxyuridine (BrdU), into the cells by in situ staining for BrdU. These experiments showed that no more than 15% of the recognizable megakaryocytes in normal bone marrow are in the process of endomitosis, including S phases interrupted by short gaps. Using immunohistochemistry, we showed that mature megakaryocytes express the G1 phase cyclin and cyclin D3, but not the mitotic cyclin, cyclin B1. Under culture conditions that selectively promote megakaryocytopoiesis, antisense oligonucleotides designed to suppress cyclin D3 expression, but not sense oligonucleotides or antisense oligonucleotides to cyclin B1, dramatically suppress endomitosis and abrogate megakaryocyte development. Our results indicate that endoreduplication in megakaryocytes is associated with low levels of or the absence of cyclin B1, whereas progression through this process depends on the G1 phase for which cyclin D3 is crucial.

Animals↗
PubMedDate not supplied

Chromosome alterations in cancer development and apoptosis.

Normal somatic cells are programmed to die (or undergo apoptosis) whereas cancer cells program themselves to survive. Some of the cytogenetic alterations that might be involved in apoptosis and continuous cell proliferation of normal and cancer cells such as shortening of telomeres, formation of dicentric chromosomes, transfer of telomeric DNA to the homologous chromosomes, malfunction (inactivation) of the centromeres, endoreduplication of chromosomes and other structural and numerical chromosome abnormalities are discussed here.

Aneuploidy↗
PubMed1978

[The mode of action of bleomycin-cell kinetic investigations (author's transl)].

Chemotherapy of malignant ENT tumours with Bleomycin (BLM) alone is not very successful. In the last time however several authors pointed out much better therapeutic results when BLM therapy has been combined with radiation treatment It is farly unknown why this combination should cause a greater therapeutic effect. Therefore we investigated the following questions: 1. In what manner does BLM influence the kinetics of cell proliferation of malignant tissues? 2. Does BLM synchronize the tumour cells or is the greater therapeutic success of a combination of BLM and X rays only depending an an additional effect? 3. Can we find a connection between the effect of BLM and the histology of the tumour? With cell kinetic methods (authoradiography, cytophotometry, mitotic index) and histological technics we examined these problems in 5 human ENT tumours and got the following results: 1. BLM initially causes a partial synchronization of the tumour cells (blockade in the S-phase). During a continuous therapy with BLM however the tumour cells will be collected in the late S- and mainly in the G2-phase. But this peak of cells in G2 is not the expression of synchronization because a lot of these cells are blocked irreversible and will leave the cell cycle (hyperceratotic cells). Ffrom those cells which thereupon have entered the mitotic phase a further part of them will by endomitosis or endoreduplication. Only a small group of the cells originally collected in the G2-phase will devide and enter the G1-phase again. Furthermore we observed a distinct recruitment of G0-cells back into the cell cycle (for details see fig. 9). 2. The greater effect of radiation therapy following the application of BLM is not the result of synchronization but of an additional destruction of premitotic G2-cells which properly would have undergone mitosis. BLM and X rays therefore act additionally. 3. The greater therapeutic success of the combination of BLM and radiation treatment comes true only in keratinizing squamous cell carcinoma. The reason is that BLM destroys the tumour cells by hyperkeratosis and polyploidy. Thus BLM must be ineffective in carcinoma without the ability of keratinizing.

Bleomycin↗
PubMed1994

[The quantitative study of the areas of active rDNA location and of the other parameters of the interphase nucleolus detectable by silver staining during the cell differentiation of the rat trophoblast].

Different quantitative parameters of nucleolar silver staining have been studied in the cambial rat trophoblast cells on the 12th, 13th and 14th days of gestation. It has been shown that the number of Ag-positive granules in the nucleoli varied from 10 to 120. The number and the total area of silver stained granules in the nuclei increased progressively in the course of polyploidization, but was not doubled passing to the next ploidy level. Nevertheless, nucleolar area increased proportionally to the ploidy degree. The mean number and the total area of Ag-stained granules as well as the nucleolar area estimated for each ploidy level did not change significantly in the course of placenta development, suggesting an unchanged level of NOR activity at the studied stages of trophoblast cell differentiation. The data obtained on the interphase nucleoli differ from the data of the analysis of the metaphase Ag-NOR at the same period of placenta development, suggesting a diversity in the interphase and metaphase NOR organization. A proportion of cells with different number of nucleoli in the cambial rat trophoblast cells was maintained unchanged in the studied period of the placenta development, the majority (80-90%) of cells contained from 1 to 3 nucleoli. Such a proportion was similar in the cells of different levels of ploidy up to 16c. In this connection the association of NORs is suggested to be in relation with switching from the polyploid mitotic cycle to the endoreduplication leading to polyteny.

Animals↗
PubMed1994

Deletion of two separate regions on chromosome 3p in breast cancers.

We have characterized the copy number of various loci on chromosome 3p in a series of breast cancers. To determine the precise region(s) involved, restriction fragment length polymorphism (RFLP) analysis for loss of heterozygosity (LOH) was performed using a panel of RFLP probes at 3p13-14, 3p21-22, and 3p24-26. The incidence of LOH at the three loci was 41, 32, and 45%, respectively. To validate the LOH data and to gain insights into the mechanisms resulting in LOH, chromosome 3 pericentromeric and 3p region-specific DNA probes were used to determine the DNA copy number by fluorescence in situ hybridization (FISH). Among 22 cases examined, 15 showed loss by both LOH and FISH, indicating that the dominant mechanism of LOH at 3p in breast cancer is a physical deletion. Two of the 22 cases showed loss by RFLP analysis but not by FISH, suggesting either mitotic recombination or loss and endoreduplication. In three cases, RFLP analysis indicated allelic imbalance, which was incorrectly interpreted as LOH, since a gain of one allele was suggested by FISH. By constructing a deletion map, we found that 2 separate regions, 3p13-14 and 3p24-26, were independently deleted in some breast cancers. Additionally, four cases had break points within the 3p24-26 region and one case had a homozygous deletion at 3p13, further supporting the hypothesis that there are tumor suppressor genes at both 3p13-14 and 3p24-26. Although high frequency of LOH was observed at the 3p21-22 region, there was no direct evidence supporting the existence of a breast cancer tumor suppressor gene there as opposed to codeletion with either the proximal or distal region.

Blotting, Southern↗
PubMed1994

Induction of differentiation and growth arrest associated with nascent (nonoligosomal) DNA fragmentation and reduced c-myc expression in MCF-7 human breast tumor cells after continuous exposure to a sublethal concentration of doxorubicin.

The effects on DNA integrity of continuous (72-h) exposure of human MCF-7 breast adenocarcinoma cells to 50 nM doxorubicin (a concentration which can be maintained in the plasma by continuous infusion) were characterized by bisbenzimide spectrofluorophotometry, cell flow cytometry, agarose gel electrophoresis, and neutral elution. Spectrofluorophotometry and cell flow cytometry indicated the presence of DNA fragmentation, which was maximal at 24 h. Resolution of these fragments on agarose gels failed to demonstrate "laddered" oligosomal profiles. Neutral elution analysis at 24 h indicated that doxorubicin induced fragmentation of nascent, but not mature, double-stranded DNA. Drug-treated cells exhibited endoreduplication and significant shifts in cell cycle distribution, (i.e., increased G0/G1 and G2/M fractions and a markedly reduced S-phase fraction). These alterations occurred without inhibiting the incorporation of [3H]dThd into cellular DNA; in fact, both the rate and magnitude of [3H]dThd incorporation increased progressively. Doxorubicin also produced a sustained decline in c-myc mRNA levels that paralleled both growth arrest and induction of DNA fragmentation. Ultrastructural examination revealed morphological alterations consistent with the induction of differentiation (e.g., increased lipid content and mitochondrial density, appearance of tight junctions, and secretory ducts) and further suggested the possibility of autocatalysis (e.g., lipofuschin-containing vacuoles). A gradual decline in cell number was observed, with loss of approximately 35% of the cell population after 72 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗