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Biomedical subjects

L Sabatier

Publications and source records attributed to L Sabatier.

At least 55 records · Page 3Linked to original sources
PubMed1995

Radiation-induced carcinogenesis: individual sensitivity and genomic instability.

In spite of a well-known relationship between exposure to radiation and increased risk for cancer development, the biological mechanisms involved in radiation-induced carcinogenesis remain poorly documented. Various hypotheses are discussed in this paper. It appears that radiation cannot be directly responsible for the numerous genetic alterations of cancer cells. Most of them occur during tumor progression. Only one or a very limited number of them was induced by radiation many years before tumor growth. This long delay is a major difficulty for experimental research and raises many questions. Recently, it has been shown that a genomic instability occurs after many generations in cells descending from irradiated cells. This instability leads to multiple genetic alterations and, preferentially, affects some chromosome structures, particularly telomeres. This kind of telomeric instability - related to the shortening of telomeric DNA sequences - has also been observed in senescent cells as well as in non-senescent cells from patients predisposed to cancer, and this process may possibly also occur in the progeny of irradiated cells.

Animals↗
PubMed1995

Chromosomal instability and alteration of telomere repeat sequences.

The very end of the chromosome is called the telomere and is composed of DNA repeat sequences and associated proteins. Genetic and biochemical analyses of this complex, the telosome, lead to the hypothesis that transcription and DNA replication are submitted to position effects mediated by the telomere proximity. Telomere length reduction and alterations of the telomeric chromatin assembly might explain the chromosome instability which occurs during the senescence and the immortalization process in vitro. A particular polymerase, the telomerase, is able to lengthen the telomeres. A telomerase activity was characterized in yeast, Tetrahymena, but also in transformed and in germline cells. We reviewed the involvement of telomeres in the aging process. We proposed that the short size of the telomere repeat at each chromosome could direct the loss of heterozygosity, thus telomere length could play a role in individual and tissular susceptibility to develop cancer. Antitelomerase strategy for cancer therapy is attractive but limited by the short decrease of the telomere length at each cell division.

Aging↗
PubMed1994

Telomere dynamics in an immortal human cell line.

The integration of transfected plasmid DNA at the telomere of chromosome 13 in an immortalized simian virus 40-transformed human cell line provided the first opportunity to study polymorphism in the number of telomeric repeat sequences on the end of a single chromosome. Three subclones of this cell line were selected for analysis: one with a long telomere on chromosome 13, one with a short telomere, and one with such extreme polymorphism that no distinct band was discernible. Further subcloning demonstrated that telomere polymorphism resulted from both gradual changes and rapid changes that sometimes involved many kilobases. The gradual changes were due to the shortening of telomeres at a rate similar to that reported for telomeres of somatic cells without telomerase, eventually resulting in the loss of nearly all of the telomere. However, telomeres were not generally lost completely, as shown by the absence of polymorphism in the subtelomeric plasmid sequences. Instead, telomeres that were less than a few hundred base pairs in length showed a rapid, highly heterogeneous increase in size. Rapid changes in telomere length also occurred on longer telomeres. The frequency of this type of change in telomere length varied among the subclones and correlated with chromosome fusion. Therefore, the rapid changes in telomere length appeared occasionally to result in the complete loss of telomeric repeat sequences. Rapid changes in telomere length have been associated with telomere loss and chromosome instability in yeast and could be responsible for the high rate of chromosome fusion observed in many human tumor cell lines.

Cell Line, Transformed↗
PubMed1994

Clonal rearrangements in human irradiated fibroblasts.

The cytogenetic dose response following in vivo localized irradiation is difficult to establish because of the occurrence of clones defined by chromosome alterations, with various proliferative rates. The biological meaning of these clones is not well understood. Two sets of experiments were performed to follow their behavior. R-banded karyotypes were established on human fibroblasts irradiated either before or after initiation of the cultures. Clones were observed in cultures developed after irradiation of biopsies, whereas irradiated cultures exhibited karyotypes with multiple non-clonal rearrangements. This difference suggests that most radiation-induced chromosome anomalies do not confer a selective advantage on the carrier cells in vitro. The appearance of clonal anomalies following biopsy irradiation would rather be a consequence of a strong selection at the time of the growth of the cells out of the explants, which would give rise to the progeny of a limited number of progenitor cells.

Cell Line, Transformed↗
PubMed1994

Gene dosage and expression, and enzyme activity of thymidine kinase and thymidylate synthase in xenografted colorectal adenocarcinomas.

Cytogenetic studies performed on human colorectal tumors have revealed 2 specific patterns of chromosomal anomalies. The major pattern, known as the monosomic type (MT), is characterized by the loss or deletion of chromosomes 18, 17 (short arm 17p) and, less frequently, 1p, 4, 15, 5 (long arm 5q) and 21. The other one, known as the trisomic type (TT), is characterized by the gain of several chromosomes: 7, 12, X, 5 and 8. Losses of chromosome 18 and of the 17p arm never coexist in TT tumors. It was observed that many chromosome losses or deletions involved genes encoding for enzymes of the de novo pathways of nucleotide synthesis. In contrast, gains involved genes encoding for enzymes of the salvage pathways of the same metabolism. This led to the hypothesis that chromosome imbalances corresponded to those of nucleotide synthesis in tumor cells. Such an interrelation was confirmed by the dosage of thymidylate synthase (TS) and thymidine kinase (TK) activities in a series of colorectal grafted tumors. This study has been expanded to a larger series of xenografted tumors (23 cases) in which both TS and TK activities were studied, in parallel with an analysis of mRNA, by Northern blotting. The amount of mRNA was found to correlate with the number of gene copies calculated from cytogenetic data, indicating a direct gene-dosage effect. It also correlated with enzyme activities, but less strongly. This suggests the existence of an efficient post-transcriptional regulation, in particular for TS, whose level of expression varies over a wide range. Such variations may explain the diversity of responses to chemotherapy.

Adenocarcinoma↗
PubMed1994

A cytogenetic study of 19 recurrent gliomas.

A cytogenetic analysis was performed on 19 recurrent gliomas all of which had been treated by radiotherapy. All cases exhibited clonal chromosomal anomalies, the tumors were classified into four categories in relation to their mono- or polyclonality and to the presence or absence of a clonal evolution. Polyclonal tumors without clonal evolution had a delay of recurrence significantly longer than monoclonal or polyclonal tumors with clonal evolution. This difference could be related to the presence of clones with different malignant potential, which could be differentiated by their pattern of chromosomal aberrations. The malignant potential of "highly malignant" clones resulted from the juxtaposition of imbalances, such as monosomy 10, as in high-grade primary gliomas, and presumably radiation-induced structural rearrangements. That of clones of low malignancy was almost limited to the presence of multiple balanced structural rearrangements, probably induced by radiation.

Adolescent↗
PubMed1994

Possible role of inner-shell ionization phenomena in cell inactivation by heavy ions.

The existence of a correlation between experimental probabilities of cell inactivation by charged particles and calculated probabilities for K-vacancy production in heavy atoms (C, N, O, P) of the DNA of cell nuclei is established. Both phenomena display a similar dependence upon the linear energy transfer (LET) of incident particles. In particular for low LET values, K cross sections for various incident ions have nearly the same functional dependence on ion-LET and for higher LET-values, K cross sections display maxima which look like those of inactivation cross sections. These characteristics are well-understood features of the K-ionization phenomenon, in particular the maxima of probability occur for projectile velocities near orbital velocities of the ejected electrons. The meaning of the observed correlation is discussed in terms of deposited energy and in the light of existing experimental results on cell inactivation by X-ray absorption at K-threshold. We consider a mechanism which has already been evoked to explain these photo-absorption experiments and which assumes that a K ionization triggers a double-strand break by Coulomb explosion and energy dissipation of Auger electrons. However, it is seen that K cross sections are important for C, N and O atoms but negligible for P atoms. Thus, the lesion considered here affects other atoms than those involved in the K-photoabsorption experiments. The lesion efficiency with respect to subsequent double-strand breakage and repair processes is not yet known, however one may suspect a direct link between DNA blunt ends possibly induced by such K ionizations and cell inactivation.

Animals↗
PubMed1994

Chromosomal instability and alterations of telomeric repeats in irradiated human fibroblasts.

In recent years, evidence has been presented suggesting that genomic instability can appear several generations after cellular exposure to radiations. Kadhim et al. (1992) have shown that irradiation by alpha-particles of Pu238 (LET = 120 keV/microns) induce a transmissible instability in mouse haematopoietic cells. Working with human dermis fibroblasts irradiated by heavy ions in a large range of LETs (386-13,600 keV/microns), we demonstrated that an instability could also be acquired by human cells and that particular chromosomes (13, 16, 1) were recurrently involved in telomeric associations (Sabatier et al. 1992). This instability resulted in specific chromosome imbalances and in a particular monosomy 13 (Martins et al. 1993). In this study, we wanted to determine whether telomeres are shortened with the appearance of the chromosomal instability. Our results show no drastic shortening of the mean length of telomeres by Southern blot. By in situ hybridization we are looking to see if chromosomes specifically involved in instability have alterations of the telomeres. We have observed large variations of the hybridization signal of individual telomeres with no telomeric sequences detectable at the junction of end to end associations.

Cell Transformation, Neoplastic↗
PubMed1993

Specific chromosome instability induced by heavy ions: a step towards transformation of human fibroblasts?

Cultures of human skin fibroblasts were exposed to heavy ions: neon (E = 10.74 MeV/u) and argon (E = 10.52 MeV/u) at fluences of 10(6), 2 x 10(6) and 4 x 10(6) and lead (E = 9.5 MeV/u) at a fluence of 2 x 10(6) particles/cm2. Cultures were further prolonged for up to 25 passages and karyotyping was performed at various times. Radiation-induced chromosome anomalies progressively decreased, became quite rare at passages 5-7 and increased at later passages. Around passages 20-25, most anomalies occurring were dicentrics, involving telomeric regions of 13p and q arms principally and to a lesser degree those of 1p, 16p and 16q arms. These non-random rearrangements paralleled the appearance of clones with unbalanced karyotypes. In particular, two independent proliferating clones were characterized by a monosomy 13. It is concluded that most chromosome lesions directly induced by heavy ions are hardly compatible with cell survival and thus disappear after a few cell generations. However, surviving cells acquire a de novo chromosome instability leading to the formation of clones with unbalanced karyotypes at late passages.

Argon↗
PubMed1993

Decrease in catalase activity and loss of the 11p chromosome arm in the course of SV40 transformation of human fibroblasts.

The activity of catalase, a key enzyme in cell detoxication of oxygen derivatives, was studied in SV40 transformed human fibroblasts. A cytogenetic study was performed in parallel to establish a quantification of 11p arm on which the corresponding gene is mapped. mRNA amounts were determined by Northern blotting. At early passages, catalase activity strongly decreased whereas the corresponding mRNA was present. No deletions of 11p arms were detected. At later passages, catalase activity remained low. 11p arm deletions were frequent, and the amount of mRNA was decreased. In these late passages, the good correlation between the number of 11p arms and catalase activity suggested a gene dosage effect. It is assumed that the decrease of catalase activity provides a selective advantage for the transformed cells. This decrease is related to a post-transcriptional change of regulation at early passages and to the loss of the corresponding gene at later passages.

Catalase↗
PubMed1992

Chromosomal anomalies in radiation-induced fibrosis in the pig.

R-banded karyotypes were established on fibroblasts from fibrotic tissues derived from experimental fibrosis induced in pigs, either surgically or by 64 Gy of gamma-rays from iridium-192. No chromosome aberrations were observed in the surgical fibrosis. In radiation-induced fibrosis, the high frequency of abnormal karyotypes and the frequent complexity of the chromosomal rearrangements suggest that the fibroblasts originated either from the 64-Gy area, or from the penumbra, but certainly not from non-irradiated areas. At early passages in vitro, almost all karyotypes were different, demonstrating a multiclonal origin of fibrotic tissue. At late passages (above 24), the situation was quite different, with the persistence of one or two clones only, demonstrating a strong selective pressure occurring in vitro.

Animals↗
PubMed1992

Early superoxide dismutase alterations during SV40-transformation of human fibroblasts.

The expression of superoxide dismutases (SOD) 1 and 2 was studied in 4 clones of human fibroblasts after their infection by simian virus 40 (SV40), in parallel with the alterations of chromosomes 21 and chromosome 6q arms, carrying the genes that encode for SOD1 and SOD2 respectively. For all clones, a similar scheme with 2 main phases was observed for both chromosome and SOD variations. The first phase, defined as the pre-crisis phase, was characterized by chromosomal instability, but maintenance of normal numbers of chromosome 6q arms and chromosomes 21. The level of SOD2 mRNA was high, while SOD2 activity and immunoreactive protein were low. SOD1 protein and activity were decreased. In the second phase, defined as the post-crisis phase, the accumulation of clonal chromosomal rearrangements led to the loss of 6q arms, while the number of chromosomes 21 remained normal. SOD2 mRNA level was decreased and SOD2 immunoreactive protein and activity remained low. SOD1 protein and activity increased with passages, reaching values similar to those of control cells at late passages. As in established SV40-transformed human fibroblast cell lines, good correlation was found between SOD2 activity and the relative number of 6q arms. These results allow us to reconstruct the sequence of events leading to the decrease of SOD2, a possible tumor-suppressor gene, during the process of SV40-transformation of human fibroblasts.

Cell Transformation, Viral↗
PubMed1992

SOD2: a new type of tumor-suppressor gene?

The activity of superoxide dismutases (SOD) 1 and 2 was analysed in correlation with mRNA and chromosome content in 6 SV40-transformed (TF) and in non-transformed (NF) human fibroblast cell lines. Total SOD activity was fairly constant, whereas the ratio SOD2/SOD1 was much lower in TF than in NF. The decrease in SOD2 activity was correlated with a low mRNA content, and with the presence of various chromosomal rearrangements leading to deletions of the long arm of chromosome 6 where the gene is mapped. In contrast, chromosome 21, carrying the gene for SOD1, was not found to be deficient and the SOD1 activity was high. This shows that in TF, the activity of SOD2 is largely determined by gene dosage. It has been proposed that SOD activity could be inversely correlated with cell proliferation, and that SOD2 activity, in particular, was related to cell differentiation. Thus, there is a cascade of events occurring in cell transformation, involving gene deregulation, chromosome (gene) deletion, low mRNA and protein content, low enzyme activity, and acquisition of growth advantage which makes the SOD2 gene a possible new type of tumor-suppressor gene.

Cell Line, Transformed↗
PubMed1991

Chromosome aberration dosimetry: addition of thymidine, an interesting mean to increase the number of dividing cells.

Addition of thymidine to culture medium commonly used by laboratories performing medical cytogenetics followed by a release of the block by 2-deoxycitidine increases greatly the mitotic index and the proportion of metaphases suitable for chromosome analysis. The benefit is, however, less evident when the method is applied to culture medium used in laboratories specialized in chromosome aberration dosimetry.

Cell Division↗
PubMed1989

The decrease of catalase or esterase D activity in patients with microdeletions of 11p or 13q does not increase their radiosensitivity.

Lymphocyte cultures from patients affected by retinoblastoma (Rb), with or without a microdeletion of chromosome 13, and Wilms tumor (WT), with a microdeletion of chromosome 11p where exposed to gamma-ray radiation during S and G2 phases. Chromatid and chromosome lesions were scored and compared to those observed in controls. No significant differences were detected, neither between patients and controls, nor between patients carrying or not a microdeletion. This lack of difference was unexpected since the genes for catalase and esterase D, also called S-formyl glutathione hydrolase, which are two detoxication enzymes, are deleted in case of microdeletion of 11p and 13q, respectively.

Acatalasia↗
PubMed1989

How are sticky chromosomes formed?

Blood lymphocytes in culture were irradiated by gamma-rays 3 h to 30 mn before harvesting. The various induced lesions were analysed, with a particular attention on sticky chromosomes, i.e. radial figures in which chromosomes are not obviously broken, but are linked by a tiny filament. Such anomalies are preferentially induced in mid to late G2-phase. They result from recombinations occurring at nonrandom chromosome regions: junction between hetero- and euchromatin, and telomeric regions. It is proposed that they are formed when double strand breaks are induced while intrachromatidic links have started to be formed in the course of chromosome condensation. If this interpretation is correct, the apparent lack of induced breakage of premitotic chromosomes is artifactual.

Cells, Cultured↗
PubMed1988

Effect of caffeine in Fanconi anemia. I. Restoration of a normal duration of G2 phase.

In Fanconi anemia (FA) cells the duration of the G2 phase of the cell cycle prolonged. Such a slowing of the G2 phase can be induced in normal cells by irradiation with gamma rays during S phase, which also further increases the duration of G2 in FA cells. The addition of caffeine during the last 7 h of culture shortens the G2 phase in both nonirradiated and irradiated FA cells. In nonirradiated normal cells it may have no effect or may increase G2 phase duration, but in irradiated normal reduces the slowing of G2 induced by the radiation. This suggests that FA cells recognize and repair preexisting DNA lesions during G2 phase and that caffeine inhibits this process. The principal anomaly in FA may be a deficient repair during S phase, as manifest in the prolonged postreplication repair period during G2 phase required to repair the larger number of lesions passing through S phase.

Anemia, Aplastic↗