| Prolonged cell cycle response of HeLa cells to low-level alkylation exposure. | |
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MedLine Citation:
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PMID: 19638578 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Alkylation chemotherapy has been a long-standing treatment protocol for human neoplasia. N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) is a direct-acting monofunctional alkylator. Temozolomide is a clinical chemotherapeutic equivalent requiring metabolic breakdown to the alkylating agent. Both chemicals have similar mechanistic efficacy against DNA mismatch repair-proficient tumor cells that lack expression of methylguanine methyltransferase. Clinically relevant concentrations of both agents affect replicating cells only after the first cell cycle. This phenomenon has been attributed to replication fork arrest at unrepaired O(6)-methyldeoxyguanine lesions mispaired with thymine during the first replication cycle. Here, we show, by several different approaches, that MNNG-treated tumor cells do not arrest within the second cell cycle. Instead, the population slowly traverses through mitosis without cytokinesis into a third cell cycle. The peak of both ssDNA and dsDNA breaks occurs at the height of the long mitotic phase. The majority of the population emerges from mitosis as multinucleated cells that subsequently undergo cell death. However, a very small proportion of cells, <1:45,000, survive to form new colonies. Taken together, these results indicate that multinucleation within the third cell cycle, rather than replication fork arrest within the second cell cycle, is the primary trigger for cell death. Importantly, multinucleation and cell death are consistently avoided by a small percentage of the population that continues to divide. This information should prove clinically relevant for the future design of enhanced cancer chemotherapeutics. |
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Authors:
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Allen G Schroering; Anbarasi Kothandapani; Steve M Patrick; Saravanan Kaliyaperumal; Vishal P Sharma; Kandace J Williams |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-07-28 |
Journal Detail:
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Title: Cancer research Volume: 69 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2009 Aug |
Date Detail:
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Created Date: 2009-07-31 Completed Date: 2009-09-11 Revised Date: 2010-09-24 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 6307-14 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, Toledo, Ohio 43614, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents, Alkylating
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pharmacology* Cell Cycle / drug effects*, genetics Cyclin B / metabolism DNA Mismatch Repair DNA Modification Methylases / deficiency DNA Repair Enzymes / deficiency Dose-Response Relationship, Drug Hela Cells Histones / metabolism Humans Methylnitronitrosoguanidine / pharmacology* Phosphorylation Tumor Suppressor Proteins / deficiency |
| Grant Support | |
ID/Acronym/Agency:
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CA106575/CA/NCI NIH HHS; CA84412/CA/NCI NIH HHS; R01 CA084412-06/CA/NCI NIH HHS; R01 CA106575-05/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents, Alkylating; 0/CDC2 protein, human; 0/Cyclin B; 0/Histones; 0/Tumor Suppressor Proteins; 70-25-7/Methylnitronitrosoguanidine; EC 2.1.1.-/DNA Modification Methylases; EC 2.1.1.63/MGMT protein, human; EC 6.5.1.-/DNA Repair Enzymes |
| Comments/Corrections | |
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