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Abstract
Experimental radioimmunotherapy delivering absorbed doses of 2.5 to 10 Gy has been shown to cause growth retardation of tumors. The purpose of this study was to elucidate the sequential molecular and cellular events occurring in HeLa Hep2 cells exposed to such doses. Dose-response curves, activation of cell cycle checkpoints, and mitotic behavior were investigated in HeLa Hep2 cells following 2.5- to 10-Gy irradiation by carrying out 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, Western blots, fluorescence-activated cell sorting analysis, and immunofluorescence stainings. Terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining was used to detect apoptosis. A G2-M arrest was shown by fluorescence-activated cell sorting analysis. p53 and p21 were found to be up-regulated but were not immediately related to the arrest. The G2-M arrest was transient and the cells reentered the cell cycle still containing unrepaired cellular damage. This premature entry caused an increase of anaphase bridges, lagging chromosomal material, and multipolar mitotic spindles as visualized by propidium iodide staining and immunofluorescence staining with alpha-tubulin and gamma-tubulin antibodies. Furthermore, a dose-dependent significant increase in centrosome numbers from 12.6+/-6.6% to 67+/-5.3% was identified as well as a dose-dependent increase of polyploid cells from 2.8+/-1.3% to 17.6+/-2.1% with the highest absorbed dose of 10 Gy. These disturbances caused the cells to progress into mitotic catastrophe and a fraction of these dying cells showed apoptotic features as displayed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining 5 to 7 days after irradiation. An absorbed dose of 2.5 to 10 Gy was shown to force HeLa Hep2 cells into mitotic catastrophe and delayed apoptosis. These might be important cell death mechanisms involved in tumor growth retardation following radioimmunotherapy of solid tumors.
Highlights
Experimental radioimmunotherapy delivering absorbed doses of 2.5 to 10 Gy has been shown to cause growth retardation of tumors
Radiation is known to exert significant effects on the progression of the cell cycle [6] and may activate the G1-S DNA damage checkpoint, in which the DNA damage is repaired before replication [7], and/or the G2-M DNA damage checkpoint, in which the repair of DNA occurs before initiation of mitosis [7]
Our results clearly show that a number of consecutive responses with putative lethal consequences can be observed in HeLa Hep2 cells following such irradiation
Summary
Experimental radioimmunotherapy delivering absorbed doses of 2.5 to 10 Gy has been shown to cause growth retardation of tumors. The G2-M arrest was transient and the cells reentered the cell cycle still containing unrepaired cellular damage This premature entry caused an increase of anaphase bridges, lagging chromosomal material, and multipolar mitotic spindles as visualized by propidium iodide staining and immunofluorescence staining with a-tubulin and g-tubulin antibodies. Conclusion: An absorbed dose of 2.5 to 10 Gy was shown to force HeLa Hep cells into mitotic catastrophe and delayed apoptosis These might be important cell death mechanisms involved in tumor growth retardation following radioimmunotherapy of solid tumors. Several types of DNA lesions are induced by ionizing radiation, including changes in the bases of the nucleic acids, singlestrand breaks, double-strand breaks, and abnormal cross-links in DNA or between DNA and cellular proteins [1] If not repaired, such lesions might be lethal for the cell or may impair the integrity of genomic DNA. Generate cells with multiple micronuclei or binucleated giant cells [13], which is defined as a mitotic catastrophe
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