• Login
    View Item 
    •   Home
    • The Manchester Institute Cancer Research UK
    • All Paterson Institute for Cancer Research
    • View Item
    •   Home
    • The Manchester Institute Cancer Research UK
    • All Paterson Institute for Cancer Research
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of ChristieCommunitiesTitleAuthorsIssue DateSubmit DateSubjectsThis CollectionTitleAuthorsIssue DateSubmit DateSubjects

    My Account

    LoginRegister

    Local Links

    The Christie WebsiteChristie Library and Knowledge Service

    Statistics

    Display statistics

    The bioreductive agent RH1 and gamma-irradiation both cause G2/M cell cycle phase arrest and polyploidy in a p53-mutated human breast cancer cell line.

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Authors
    Kim, Joo-Young
    Kim, Chul-Hwan
    Stratford, Ian J
    Patterson, Adam V
    Hendry, Jolyon H
    Affiliation
    Cancer Research UK Group of Experimental Radiation Oncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK. jooyoungcasa@ncc.re.kr
    Issue Date
    2004-02-01
    
    Metadata
    Show full item record
    Abstract
    PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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). CONCLUSIONS: 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.
    Citation
    The bioreductive agent RH1 and gamma-irradiation both cause G2/M cell cycle phase arrest and polyploidy in a p53-mutated human breast cancer cell line. 2004, 58 (2):376-85 Int. J. Radiat. Oncol. Biol. Phys.
    Journal
    International Journal of Radiation Oncology, Biology, Physics
    URI
    http://hdl.handle.net/10541/78386
    PubMed ID
    14751506
    Type
    Article
    Language
    en
    ISSN
    0360-3016
    Collections
    All Paterson Institute for Cancer Research

    entitlement

    Related articles

    • Cytotoxicity of the bioreductive agent RH1 and its lack of interaction with radiation.
    • Authors: Kim JY, West CM, Valentine H, Ward TH, Patterson AV, Stratford IJ, Roberts SA, Hendry JH
    • Issue date: 2004 Mar
    • UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53.
    • Authors: Wang Q, Fan S, Eastman A, Worland PJ, Sausville EA, O'Connor PM
    • Issue date: 1996 Jul 17
    • G2/M-phase arrest and death by apoptosis of HL60 cells irradiated with exponentially decreasing low-dose-rate gamma radiation.
    • Authors: Ning S, Knox SJ
    • Issue date: 1999 Jun
    • Effect of pentoxifylline on radiation-induced G2-phase delay and radiosensitivity of human colon and cervical cancer cells.
    • Authors: Li YX, Weber-Johnson K, Sun LQ, Paschoud N, Mirimanoff RO, Coucke PA
    • Issue date: 1998 Apr
    • Deregulation of p53/p21Cip1/Waf1 pathway contributes to polyploidy and apoptosis of E1A+cHa-ras transformed cells after gamma-irradiation.
    • Authors: Bulavin DV, Tararova ND, Aksenov ND, Pospelov VA, Pospelova TV
    • Issue date: 1999 Oct 7
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Contact Us
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.