title: Targeting Hypoxic Prostate Tumors Using the Novel Hypoxia-Activated Prodrug OCT1002 Inhibits Expression of Genes Associated with Malignant Progression.
abstract: Purpose:To understand the role of hypoxia in prostate tumor progression and to evaluate the ability of the novel unidirectional hypoxia-activated prodrug OCT1002 to enhance the antitumor effect of bicalutamide.Experimental Design:The effect of OCT1002 on prostate cancer cells (LNCaP, 22Rv1, and PC3) was measured in normoxia and hypoxiain vitroIn vivo, tumor growth and lung metastases were measured in mice treated with bicalutamide, OCT1002, or a combination. Dorsal skin fold chambers were used to image tumor vasculaturein vivoLongitudinal gene expression changes in tumors were analyzed using PCR.Results:Reduction of OCT1002 to its active form (OCT1001) decreased prostate cancer cell viability. In LNCaP-luc spheroids, OCT1002 caused increased apoptosis and decreased clonogenicity.In vivo, treatment with OCT1002 alone, or with bicalutamide, showed significantly greater tumor growth control and reduced lung metastases compared with controls. Reestablishment of the tumor microvasculature following bicalutamide-induced vascular collapse is inhibited by OCT1002. Significantly, the upregulation ofRUNX2and its targets caused by bicalutamide alone was blocked by OCT1002.Conclusions:OCT1002 selectively targets hypoxic tumor cells and enhances the antitumor efficacy of bicalutamide. Furthermore, bicalutamide caused changes in gene expression, which indicated progression to a more malignant genotype; OCT1002 blocked these effects, emphasizing that more attention should be attached to understanding genetic changes that may occur during treatment. Early targeting of hypoxic cells with OCT1002 can provide a means of inhibiting prostate tumor growth and malignant progression. This is of importance for the design and refinement of existing androgen-deprivation regimens in the clinic.Clin Cancer Res; 23(7); 1797-808. ©2016 AACR.
authors.affiliation: Biomedical Sciences Research Institute, University of Ulster, Cromore Road, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Heather
authors.initials: H
authors.lastname: Nesbitt
authors.affiliation: Biomedical Sciences Research Institute, University of Ulster, Cromore Road, Coleraine, Northern Ireland, United Kingdom.|Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Niall M
authors.initials: NM
authors.lastname: Byrne
authors.affiliation: Axis Bioservices Ltd, Coleraine, Northern Ireland, United Kingdom.
authors.forename: S Nicole
authors.initials: SN
authors.lastname: Williams
authors.affiliation: Biomedical Sciences Research Institute, University of Ulster, Cromore Road, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: Ming
authors.affiliation: Biomedical Sciences Research Institute, University of Ulster, Cromore Road, Coleraine, Northern Ireland, United Kingdom.|Axis Bioservices Ltd, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Jenny
authors.initials: J
authors.lastname: Worthington
authors.affiliation: School of Medicine, Cardiff University, Cardiff, United Kingdom.|BioStatus Ltd, Shepshed, Leicestershire, United Kingdom.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Errington
authors.affiliation: OncoTherics Ltd, Shepshed, Leicestershire, United Kingdom.
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Patterson
authors.affiliation: OncoTherics Ltd, Shepshed, Leicestershire, United Kingdom.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: Biomedical Sciences Research Institute, University of Ulster, Cromore Road, Coleraine, Northern Ireland, United Kingdom.|OncoTherics Ltd, Shepshed, Leicestershire, United Kingdom.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: McKeown
authors.affiliation: Biomedical Sciences Research Institute, University of Ulster, Cromore Road, Coleraine, Northern Ireland, United Kingdom. dj.mckenna@ulster.ac.uk.
authors.forename: Declan J
authors.initials: DJ
authors.lastname: McKenna
mesh_terms: D000813:Anilides / Q000008:administration & dosage; D000818:Animals; D000880:Anthraquinones / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D005029:Ethylenediamines / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics*; D009570:Nitriles / Q000008:administration & dosage; D011355:Prodrugs / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014105:Tosyl Compounds / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000880:Anthraquinones; D050659:Core Binding Factor Alpha 1 Subunit; D005029:Ethylenediamines; D009363:Neoplasm Proteins; D009570:Nitriles; C000624405:OCT1002; D011355:Prodrugs; C493709:RUNX2 protein, human; D014105:Tosyl Compounds; C053541:bicalutamide