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PubMed:14751506 JSONTXT

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PubMed_Structured_Abstracts

Id Subject Object Predicate Lexical cue
T1 161-1023 OBJECTIVE denotes RH1 is a newly developed bioreductive agent, and its bioactivation is mediated by the enzyme DT-diaphorase (DTD). We have shown previously that RH1 is highly cytotoxic against cells expressing high DTD, using the p53-mutated MDA231 human breast cancer cell line transfected with the DTD gene (D7 cells). We now report that both RH1 and gamma-irradiation cause D7 cells to arrest in the G2/M cell cycle phase and undergo polyploidy. The latter is a way of p53-mutated cells responding to DNA-damaging agents. Only a small proportion of the polyploid cells are clonogenic, hence polyploidy may contribute to the reproductive failure of the cells after RH1 and irradiation. Thus, we investigated the effect of RH1 and gamma-irradiation on the formation of polyploid cells and a sub-G1 population (as a measure of apoptosis) in relation to the G2/M cell cycle block.
T2 1047-1445 METHODS denotes MDA231 D7 cells were treated using a range of RH1 doses. The cells were irradiated using 2 Gy or 5 Gy gamma-rays either as a single dose or in combination with RH1. An IC(90) dose (dose to kill 90% of the cells) of RH1 was administered for 3 h followed by irradiation after a further 24 h. Subsequent changes in cell cycle and polyploidy (DNA content in excess of that of G2/M cells) were examined.
T3 1455-3050 RESULTS denotes Treatment of D7 cells with the RH1 resulted in 60-70% of cells arrested in the G2/M phase of the cell cycle by 24 h, which decreased to control levels by 48 h. Irradiation with 2 Gy and 5 Gy caused a similar G2/M block at 12-24 h, which was followed by a sharp decline at 24-48 h. In contrast, the same dose of radiation combined with RH1 held the cells in the G2/M phase up to 48 h, and this pattern reached pretreatment levels at 72-96 h. Most control cells were found to contain a small number of spontaneously arising polyploid cells. The development of polyploid cells was evident from 12 h after all treatments and showed a significant increase at 48 h and subsequently. As opposed to this, apoptosis measured by the sub-G1 cell population in DNA analyses showed a tendency to increase according to the elapsed time for each group of treatments. Single treatments with RH1 caused a significant increase in the apoptotic population between 48 and 120 h. The first significant increase in apoptosis was observed at 48 h for 5 Gy, 2 Gy + RH1, and 5 Gy + RH1 treatments, and showed a tendency to increase further at later times, but the 2 Gy dose gave an earlier apoptotic peak at 24 h, which decreased to 96 h. The addition of RH1 to the irradiation did not increase the formation of polyploid cells or apoptosis compared with radiation alone (2 Gy vs. RH1 + 2 Gy or 5 Gy vs. RH1 + 5 Gy). The higher dose of irradiation (5 Gy vs. 2 Gy) resulted in a significantly higher proportion of polyploid cells (but not of apoptotic cells) when used alone or in combination (5 Gy + RH1 vs. 2 Gy + RH1).
T4 3064-3657 CONCLUSIONS denotes Both RH1 and gamma-irradiation, individually and in combination, showed a significant G2/M block in MDA231 D7 breast cancer cells. The formation of polyploid cells was dependent more on the radiation dose rather than on the pretreatment with RH1. The polyploid cell population was observed after the G2/M cell cycle phase arrest, and it preceded the late increase of the apoptotic cell population. The role of polyploidy in cell reproductive failure in the total cell population is not known, but it appears to contribute to cytotoxicity in cells released from the G2/M cell cycle phase block.

PubmedHPO

Id Subject Object Predicate Lexical cue
T1 399-412 HP_0003002 denotes breast cancer
T2 399-412 HP_0100013 denotes breast cancer
T3 406-412 HP_0002664 denotes cancer

DisGeNET5_gene_disease

Id Subject Object Predicate Lexical cue
14751506-2#84#87#gene1728 359-362 gene1728 denotes DTD
14751506-2#169#172#gene1728 444-447 gene1728 denotes DTD
14751506-2#124#137#diseaseC0006142 399-412 diseaseC0006142 denotes breast cancer
14751506-2#124#137#diseaseC0678222 399-412 diseaseC0678222 denotes breast cancer
14751506-2#124#137#diseaseC0006142 399-412 diseaseC0006142 denotes breast cancer
14751506-2#124#137#diseaseC0678222 399-412 diseaseC0678222 denotes breast cancer
84#87#gene1728124#137#diseaseC0006142 14751506-2#84#87#gene1728 14751506-2#124#137#diseaseC0006142 associated_with DTD,breast cancer
84#87#gene1728124#137#diseaseC0678222 14751506-2#84#87#gene1728 14751506-2#124#137#diseaseC0678222 associated_with DTD,breast cancer
84#87#gene1728124#137#diseaseC0006142 14751506-2#84#87#gene1728 14751506-2#124#137#diseaseC0006142 associated_with DTD,breast cancer
84#87#gene1728124#137#diseaseC0678222 14751506-2#84#87#gene1728 14751506-2#124#137#diseaseC0678222 associated_with DTD,breast cancer
169#172#gene1728124#137#diseaseC0006142 14751506-2#169#172#gene1728 14751506-2#124#137#diseaseC0006142 associated_with DTD,breast cancer
169#172#gene1728124#137#diseaseC0678222 14751506-2#169#172#gene1728 14751506-2#124#137#diseaseC0678222 associated_with DTD,breast cancer
169#172#gene1728124#137#diseaseC0006142 14751506-2#169#172#gene1728 14751506-2#124#137#diseaseC0006142 associated_with DTD,breast cancer
169#172#gene1728124#137#diseaseC0678222 14751506-2#169#172#gene1728 14751506-2#124#137#diseaseC0678222 associated_with DTD,breast cancer

DisGeNET

Id Subject Object Predicate Lexical cue
T0 444-447 gene:1728 denotes DTD
T1 399-412 disease:C0006142 denotes breast cancer
T2 444-447 gene:1728 denotes DTD
T3 399-412 disease:C0678222 denotes breast cancer
R1 T0 T1 associated_with DTD,breast cancer
R2 T2 T3 associated_with DTD,breast cancer