title: Genotoxicity studies on DNA-interactive telomerase inhibitors with application as anti-cancer agents.
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.
authors.affiliation: Department of Biomedical Sciences, University of Bradford, Bradford, United Kingdom.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Harrington
authors.forename: Eduardo
authors.initials: E
authors.lastname: Cemeli
authors.forename: Joanna
authors.initials: J
authors.lastname: Carder
authors.forename: Jamie
authors.initials: J
authors.lastname: Fearnley
authors.forename: Sian
authors.initials: S
authors.lastname: Estdale
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Perry
authors.forename: Terence C
authors.initials: TC
authors.lastname: Jenkins
authors.forename: Diana
authors.initials: D
authors.lastname: Anderson
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D020552:Comet Assay; D004249:DNA Damage; D004260:DNA Repair; D004269:DNA, Bacterial / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005449:Fluorenes / Q000633:toxicity; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D009152:Mutagenicity Tests; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004269:DNA, Bacterial; D004791:Enzyme Inhibitors; D005449:Fluorenes; D019098:Telomerase