| Literature DB >> 26474663 |
Erica L Stone1, Francesca Citossi1, Rajinder Singh2, Balvinder Kaur2, Margaret Gaskell2, Peter B Farmer2, Anne Monks3, Curtis Hose3, Malcolm F G Stevens1, Chee-Onn Leong4, Michael Stocks1, Barrie Kellam1, Maria Marlow1, Tracey D Bradshaw1.
Abstract
Potent, selective antitumour AhR ligands 5F 203 and GW 610 are bioactivated by CYPs 1A1 and 2W1. Herein we reason that DNA adducts' generation resulting in lethal DNA double strand breaks (DSBs) underlies benzothiazoles' activity. Treatment of sensitive carcinoma cell lines with GW 610 generated co-eluting DNA adducts (R(2)>0.7). Time-dependent appearance of γ-H2AX foci revealed subsequent DNA double strand breaks. Propensity for systemic toxicity of benzothiazoles steered development of prodrugs' hydrogels for localised delivery. Clinical applications of targeted therapies include prevention or treatment of recurrent disease after surgical resection of solid tumours. In vitro evaluation of 5F 203 prodrugs' activity demonstrated nanomolar potency against MCF-7 breast and IGROV-1 ovarian carcinoma cell lines.Entities:
Keywords: 5F 203; Antitumour benzothiazoles; DNA adducts; DNA double strand breaks; GW 610; Low molecular weight gelators (LMWGs)
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Year: 2015 PMID： 26474663 DOI： 10.1016/j.bmc.2015.09.052
Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641