The Experts below are selected from a list of 36 Experts worldwide ranked by ideXlab platform
Julian R Preston - One of the best experts on this subject based on the ideXlab platform.
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increased sensitivity to Chromatid Aberration induction by bleomycin and neocarzinostatin results from alterations in a dna damage response pathway
Mutation Research, 2000Co-Authors: Theresa Allio, Julian R PrestonAbstract:Abstract DNA damage response pathways coordinate the cellular response to DNA damage. To investigate the roles of tumor suppressor genes in these pathways, human lymphoblastoid cells (wild-type, p53−/− , ATM−/− ) were treated for 1 h with 0–3 μg/ml of the radiomimetic compound bleomycin (BLM), and cells treated in G 2 were analyzed for Chromatid Aberrations. BLM-induced Aberration frequencies were significantly increased, to the greatest extent in the ATM−/− cells and, to a lesser extent, in the p53−/− cells compared to wild-type cells. These observations are consistent with p53 and ATM acting in a damage response pathway activated by DNA strand breaks. The consequences of disrupting this pathway were further investigated by studies using wortmannin, a PI-3 kinase and DNA repair inhibitor. Wortmannin significantly increased the BLM-induced Aberration frequencies in all but the ATM−/− cells, elevating the sensitivity of p53−/− cells to ATM−/− levels and that of wild-type cells to intermediate levels. These differential sensitivities suggest that the ATM phenotype is the result of dual cellular defects, one involving p53 and the other a wortmannin-sensitive component. Similar studies in Brca1+/− and Brca2+/− human lymphoblasts showed no increased sensitization to BLM in the absence of inhibitor, and differential sensitization by wortmannin. To determine if there was any substrate specificity for p53- and ATM-mediated DNA damage responses, Chromatid Aberrations were assessed in wild-type, p53−/− , and ATM−/− cells exposed to 0–0.4 μg/ml neocarzinostatin (NCS) for 1 h. In contrast to results with BLM, the p53−/− cells exhibited a low sensitivity to NCS-induced Aberrations, similar to wild-type, while ATM−/− cells remained highly sensitive. This suggests that the response to BLM- and NCS-induced lesions involves different mechanisms.
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the relationship between p53 status dna repair and Chromatid Aberration induction in g2 mouse embryo fibroblast cells treated with bleomycin
Carcinogenesis, 1996Co-Authors: Maria E Donner, Julian R PrestonAbstract:The involvement of p53 in the formation of chromosome Aberrations was assessed by analyzing bleomycin-induced, Chromatid-type Aberrations in G 2 phase fibroblasts derived from embryos from wild-type and p53 knock-out mice. Cells that were p53+/- or p53-/- were more sensitive to the induction of Aberrations than the p53+/+ cells, particularly at concentrations of 7.5 and 10.0 μg/ml. The p53-deficient cells also showed an overdispersed distribution of bleomycin-induced Chromatid Aberrations, a greater amount of overall genomic instability and a possible loss of a cell death pathway. These data are interpreted as indicating a role for p53 in DNA repair in the G 2 phase, with a loss of p53 leading to an increased frequency of deletions (incomplete repair) and interchanges (misrepair). The specific role remains to be elucidated. The mitotic index decreased with increasing bleomycin concentration to a similar extent in all three cell lines, indicating that the loss of a G 2 checkpoint in p53-/- and p53+/- cells was not an explanation for the increased sensitivities in these cells compared with the p53+/+.
Hans G Drexler - One of the best experts on this subject based on the ideXlab platform.
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Chromatid Aberration dose responses and dispersal in human g2 lymphocytes treated with bleomycin comparison with equivalent x irradiation reveals formation of a novel class of heavily damaged cells
Mutation Research, 1994Co-Authors: Roderick A F Macleod, Maren Voges, Peter E Bryant, Hans G DrexlerAbstract:Abstract We describe the dose responses and dispersal of Chromatid (ct) Aberrations in human peripheral blood lymphocytes, treated with a 5-min pulse of bleomycin (BLM) in doses ranging from 0.78 to 200 μg/ml during the G 2 phase of the cell cycle. Damage was assessed in cells fixed at the time of peak damage 1 h after treatment. Both ct breaks and the percentages of damaged cells rose according to log BLM dose damage 6.3 μg/ml only. Below this dose all endpoints exhibited flat responses suggestive of thresholding. A dose of 100 μg/ml produced similar amounts and distribution of ct breakage (B/c) as a previously studied X-ray dose of 0.8 Gy, permitting future direct cytogenetic comparisons between clastogens. Within the scorable range (0–29 B/c) the dispersal of ct breakage after BLM treatment resembled that after equivalent X-irradiation; but BLM treatment alone resulted in the formation of heavily damaged cells (HDC) defined as with ≥ 30 b/c, representing a cytogenetic endpoint of DNA damage reminiscent of apoptosis. At the dose producing equivalent Chromatid breakage, BLM produced 7.4 times fewer exchanges than X-rays in G 2 .
Theresa Allio - One of the best experts on this subject based on the ideXlab platform.
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increased sensitivity to Chromatid Aberration induction by bleomycin and neocarzinostatin results from alterations in a dna damage response pathway
Mutation Research, 2000Co-Authors: Theresa Allio, Julian R PrestonAbstract:Abstract DNA damage response pathways coordinate the cellular response to DNA damage. To investigate the roles of tumor suppressor genes in these pathways, human lymphoblastoid cells (wild-type, p53−/− , ATM−/− ) were treated for 1 h with 0–3 μg/ml of the radiomimetic compound bleomycin (BLM), and cells treated in G 2 were analyzed for Chromatid Aberrations. BLM-induced Aberration frequencies were significantly increased, to the greatest extent in the ATM−/− cells and, to a lesser extent, in the p53−/− cells compared to wild-type cells. These observations are consistent with p53 and ATM acting in a damage response pathway activated by DNA strand breaks. The consequences of disrupting this pathway were further investigated by studies using wortmannin, a PI-3 kinase and DNA repair inhibitor. Wortmannin significantly increased the BLM-induced Aberration frequencies in all but the ATM−/− cells, elevating the sensitivity of p53−/− cells to ATM−/− levels and that of wild-type cells to intermediate levels. These differential sensitivities suggest that the ATM phenotype is the result of dual cellular defects, one involving p53 and the other a wortmannin-sensitive component. Similar studies in Brca1+/− and Brca2+/− human lymphoblasts showed no increased sensitization to BLM in the absence of inhibitor, and differential sensitization by wortmannin. To determine if there was any substrate specificity for p53- and ATM-mediated DNA damage responses, Chromatid Aberrations were assessed in wild-type, p53−/− , and ATM−/− cells exposed to 0–0.4 μg/ml neocarzinostatin (NCS) for 1 h. In contrast to results with BLM, the p53−/− cells exhibited a low sensitivity to NCS-induced Aberrations, similar to wild-type, while ATM−/− cells remained highly sensitive. This suggests that the response to BLM- and NCS-induced lesions involves different mechanisms.
Roderick A F Macleod - One of the best experts on this subject based on the ideXlab platform.
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Chromatid Aberration dose responses and dispersal in human g2 lymphocytes treated with bleomycin comparison with equivalent x irradiation reveals formation of a novel class of heavily damaged cells
Mutation Research, 1994Co-Authors: Roderick A F Macleod, Maren Voges, Peter E Bryant, Hans G DrexlerAbstract:Abstract We describe the dose responses and dispersal of Chromatid (ct) Aberrations in human peripheral blood lymphocytes, treated with a 5-min pulse of bleomycin (BLM) in doses ranging from 0.78 to 200 μg/ml during the G 2 phase of the cell cycle. Damage was assessed in cells fixed at the time of peak damage 1 h after treatment. Both ct breaks and the percentages of damaged cells rose according to log BLM dose damage 6.3 μg/ml only. Below this dose all endpoints exhibited flat responses suggestive of thresholding. A dose of 100 μg/ml produced similar amounts and distribution of ct breakage (B/c) as a previously studied X-ray dose of 0.8 Gy, permitting future direct cytogenetic comparisons between clastogens. Within the scorable range (0–29 B/c) the dispersal of ct breakage after BLM treatment resembled that after equivalent X-irradiation; but BLM treatment alone resulted in the formation of heavily damaged cells (HDC) defined as with ≥ 30 b/c, representing a cytogenetic endpoint of DNA damage reminiscent of apoptosis. At the dose producing equivalent Chromatid breakage, BLM produced 7.4 times fewer exchanges than X-rays in G 2 .
Peter E Bryant - One of the best experts on this subject based on the ideXlab platform.
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Chromatid Aberration dose responses and dispersal in human g2 lymphocytes treated with bleomycin comparison with equivalent x irradiation reveals formation of a novel class of heavily damaged cells
Mutation Research, 1994Co-Authors: Roderick A F Macleod, Maren Voges, Peter E Bryant, Hans G DrexlerAbstract:Abstract We describe the dose responses and dispersal of Chromatid (ct) Aberrations in human peripheral blood lymphocytes, treated with a 5-min pulse of bleomycin (BLM) in doses ranging from 0.78 to 200 μg/ml during the G 2 phase of the cell cycle. Damage was assessed in cells fixed at the time of peak damage 1 h after treatment. Both ct breaks and the percentages of damaged cells rose according to log BLM dose damage 6.3 μg/ml only. Below this dose all endpoints exhibited flat responses suggestive of thresholding. A dose of 100 μg/ml produced similar amounts and distribution of ct breakage (B/c) as a previously studied X-ray dose of 0.8 Gy, permitting future direct cytogenetic comparisons between clastogens. Within the scorable range (0–29 B/c) the dispersal of ct breakage after BLM treatment resembled that after equivalent X-irradiation; but BLM treatment alone resulted in the formation of heavily damaged cells (HDC) defined as with ≥ 30 b/c, representing a cytogenetic endpoint of DNA damage reminiscent of apoptosis. At the dose producing equivalent Chromatid breakage, BLM produced 7.4 times fewer exchanges than X-rays in G 2 .