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    Genotoxicity studies on DNA-interactive telomerase inhibitors with application as anti-cancer agents

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    Publication date
    2003-12
    Author
    Harrington, Dean J.
    Cemeli, Eduardo
    Carder, Joanna
    Fearnley, Jamie
    Estdale, Siân E.
    Perry, Philip J.
    Jenkins, Terence C.
    Anderson, Diana
    Keyword
    Ames test; Comet assay; Telomerase inhibitors; Anti-cancer drugs; Quinones
    Peer-Reviewed
    Yes
    
    Metadata
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    Abstract
    Telomerase-targeted strategies have aroused recent interest in anti-cancer chemotherapy, because DNA-binding drugs can interact with high-order tetraplex rather than double-stranded (duplex) DNA targets in tumour cells. However, the protracted cell-drug exposure times necessary for clinical application require that telomerase inhibitory efficacy must be accompanied by both low inherent cytotoxicity and the absence of mutagenicity/genotoxicity. For the first time, the genotoxicity of a number of structurally diverse DNA-interactive telomerase inhibitors is examined in the Ames test using six Salmonella typhimurium bacterial strains (TA1535, TA1537, TA1538, TA98, TA100, and TA102). DNA damage induced by each agent was also assessed using the Comet assay with human lymphocytes. The two assay procedures revealed markedly different genotoxicity profiles that are likely to reflect differences in metabolism and/or DNA repair between bacterial and mammalian cells. The mutational spectrum for a biologically active fluorenone derivative, shown to be mutagenic in the TA100 strain, was characterised using a novel and rapid assay method based upon PCR amplification of a fragment of the hisG46 allele, followed by RFLP analysis. Preliminary analysis indicates that the majority (84%) of mutations induced by this compound are C→A transversions at position 2 of the missense proline codon of the hisG46 allele. However, despite its genotoxic bacterial profile, this fluorenone agent gave a negative response in the Comet assay, and demonstrates how unwanted systemic effects (e.g., cytotoxicity and genotoxicity) can be prevented or ameliorated through suitable molecular fine-tuning of a candidate drug in targeted human tumour cells.
    URI
    http://hdl.handle.net/10454/11585
    Version
    No full-text in the repository
    Citation
    Harrington DJ, Cemeli E, Carder J et al (2003) Genotoxicity studies on DNA-interactive telomerase inhibitors with application as anti-cancer agents. Teratogenesis, Carcinogenesis, and Mutagenesis. 23(S2): 31-41.
    Link to publisher’s version
    http://dx.doi.org/10.1002/tcm.10082
    Type
    Article
    Collections
    Life Sciences Publications

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