Heterogeneity in the radiosensitizing effects of the DNA ligand hoechst-33342 in human tumor cell lines.

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dc.contributor.authorAdhikari, J Sen_US
dc.contributor.authorKhaitan, Divyaen_US
dc.contributor.authorArya, M Ben_US
dc.contributor.authorDwarakanath, B Sen_US
dc.date.accessioned2005-07-14en_US
dc.date.accessioned2009-06-01T16:19:31Z
dc.date.available2005-07-14en_US
dc.date.available2009-06-01T16:19:31Z
dc.date.issued2005-07-14en_US
dc.description.abstractThe AT specific minor grove DNA binding ligands bisbenzimidazole derivatives like hoechst-33342 and hoechst-33258 which scavenge free radicals and stabilize macromolecular structure have been shown to afford radioprotection by reducing the induction of DNA damage. However, their ability to inhibit topoisomerases I & II, which play important roles in damage response pathways including DNA repair can enhance radiation damage under certain conditions. Since pool sizes of the topoisomerases differ not only between normal and tumor cells, but also among different tumors, it is anticipated that radiosensitization by hoechst-33342 can vary among tumors. The present studies were, therefore, undertaken to verify this proposition in human glioma (BMG-1 &U-87) and squamous carcinoma (4197 &4451) cell lines which differ in their biological behavior (ploidy, p53, cyclins, bcl, bax etc). Isotoxic concentrations of hoechst-33342 (IC50 i.e producing 50% cell kill) administered immediately following irradiation resulted in the radiosensitization of all cell lines, with a 4&7 fold increase in the cell death (loss of clonogenic cell survival) in U-87&BMG-1 and a 3 fold increase in 4197 &4451 cells. Growth inhibition and increase in cytogenetic damage (micronuclei formation) as well as delayed apoptosis observed under these conditions corroborated well with the enhanced cell death. The ligand induced a significant cell cycle delay, particularly in the late S and G2 phases of BMG-1, U-87 and 4197 cells, while no significant changes could be observed in 4451 cells. Higher endogenous levels of cyclin B1 found in both the glioma cell lines, was enhanced further by the ligand as compared to the squamous carcinoma cells. These results clearly demonstrate that the radiosensitizing effects of the ligand are indeed heterogeneous among different human tumor cell lines. The radiaosensitization is p53 independent and accompanied by enhanced mitotic death (linked to cytogenetic damage) as well as induction of cyclin B1 mediated apoptosis.en_US
dc.description.affiliationDivision of Biocybernetics, Institute of Nuclear Medicine and Allied Sciences, Delhi, India.en_US
dc.identifier.citationAdhikari JS, Khaitan D, Arya MB, Dwarakanath BS. Heterogeneity in the radiosensitizing effects of the DNA ligand hoechst-33342 in human tumor cell lines. Journal of Cancer Research and Therapeutics. 2005 Jul-Sep; 1(3): 151-61en_US
dc.identifier.urihttps://imsear.searo.who.int/handle/123456789/111469
dc.language.isoengen_US
dc.source.urihttps://www.cancerjournal.neten_US
dc.subject.meshApoptosis --drug effectsen_US
dc.subject.meshBenzimidazoles --pharmacologyen_US
dc.subject.meshCarcinoma, Squamous Cell --pathologyen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCell Proliferation --drug effectsen_US
dc.subject.meshCell Survival --drug effectsen_US
dc.subject.meshCyclin B --biosynthesisen_US
dc.subject.meshDNA Damageen_US
dc.subject.meshGlioma --pathologyen_US
dc.subject.meshHumansen_US
dc.subject.meshMicronuclei, Chromosome-Defectiveen_US
dc.subject.meshRadiation-Sensitizing Agents --pharmacologyen_US
dc.titleHeterogeneity in the radiosensitizing effects of the DNA ligand hoechst-33342 in human tumor cell lines.en_US
dc.typeJournal Articleen_US
dc.typeResearch Support, Non-U.S. Gov'ten_US
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