title: Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery.
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.
authors.affiliation: School of Pharmacy, University of Nottingham, NG7 2RD, UK.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Stone
authors.affiliation: School of Pharmacy, University of Nottingham, NG7 2RD, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Citossi
authors.affiliation: Biocentre, University of Leicester, LE1 7RH, UK.
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.affiliation: Biocentre, University of Leicester, LE1 7RH, UK.
authors.forename: Balvinder
authors.initials: B
authors.lastname: Kaur
authors.affiliation: Biocentre, University of Leicester, LE1 7RH, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Gaskell
authors.affiliation: Biocentre, University of Leicester, LE1 7RH, UK.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Farmer
authors.affiliation: National Cancer Institute, Frederick, MD 21702-1202, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Monks
authors.affiliation: National Cancer Institute, Frederick, MD 21702-1202, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Hose
authors.affiliation: School of Pharmacy, University of Nottingham, NG7 2RD, UK.
authors.forename: Malcolm F G
authors.initials: MF
authors.lastname: Stevens
authors.affiliation: School of Pharmacy and Health Sciences, International Medical University, 57000 Kuala Lumpur, Malaysia.
authors.forename: Chee-Onn
authors.initials: CO
authors.lastname: Leong
authors.affiliation: School of Pharmacy, University of Nottingham, NG7 2RD, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Stocks
authors.affiliation: School of Pharmacy, University of Nottingham, NG7 2RD, UK.
authors.forename: Barrie
authors.initials: B
authors.lastname: Kellam
authors.affiliation: School of Pharmacy, University of Nottingham, NG7 2RD, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Marlow
authors.affiliation: School of Pharmacy, University of Nottingham, NG7 2RD, UK.
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Bradshaw
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D018613:Microscopy, Confocal; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C507816:2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole; C425784:2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D018736:DNA Adducts; C468783:H2AX protein, human; D006657:Histones; D020100:Hydrogels; D011355:Prodrugs; D013267:Stilbenes; D013844:Thiazoles; D019363:Cytochrome P-450 CYP1A1; D000077185:Resveratrol
keywords: 5F 203; Antitumour benzothiazoles; DNA adducts; DNA double strand breaks; GW 610; Low molecular weight gelators (LMWGs)