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Cytometry of Anticancer Prodrug OCT1002 Activation and Targeting Using In Vitro and In Vivo Models of Tumour Hypoxia

Smith, Paul, Wiltshire, Marie, Nesbitt, Heather, Byrne, Niall, Ming, Louise, McKenna, Declan, Worthington, Jenny, McKeown, Stephanie, Patterson, Laurence and Errington, Rachel (2015) Cytometry of Anticancer Prodrug OCT1002 Activation and Targeting Using In Vitro and In Vivo Models of Tumour Hypoxia. In: CYTO 2015, the 30th Congress of the International Society for Advancement of Cytometry, Glasgow,Scotland. International Society for Advancement of Cytometry. 268 pp. [Conference contribution]

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URL: http://cytoconference.org/CMSPages/GetFile.aspx?nodeguid=40894822-ab2f-4a38-ad31-e72312f926f5&lang=en-US

Abstract

Background: Tumour microenvironment hypoxia (TMH)facilitates disease progression and therapeutic resistance,presenting challenges for the treatment of prostate and pancreaticcancer. The non-toxic anthraquinone prodrug OCT1002(OncoTherics, UK) is designed to distribute widely in tissues,become irreversibly activated to OCT1001, a potent DNAtopoisomerase II inhibitor, thereby acting as unidirectionalhypoxia activated prodrug (uHAP). We have investigated therelationship between intracellular generation and persistence ofTMH-generated OCT1001 and biological responses both in vitroand in vivo.Methods: Confocal imaging and FCM exploited the intrinsic farredfluorescence of the uHAP. Cancer cell lines were exposed toclinically relevant prodrug levels at 1-100 nM under hypoxia (4d;1-3% oxygen); studied for cell proliferation, OCT1002bioreduction and cell cycle arrest. Human prostate cancerxenografts expressing a luciferase reporter (LNCaP-luc) in Balb/cSCID mice were used to monitor growth delay, lung metastasisand vascular changes in relation to OCT1002 targeting in dorsalskin-flap/window chambers. pO2 of tumours was recorded usingan Oxylite 2000 system and assessed in tissues by Glut1 staining.Xenograft induced hypoxia was achieved by exposure tobicalutamide (Casodex™; a non-steroidal anti-androgen).Pancreatic cancer human BX-PC3/SCID mouse xenografts,presenting intrinsic hypoxia, were used to assess uHAPmonotherapy.Results: Hypoxia-dependent growth arrest induced by OCT1002was found in a wide range cancer cell lines irrespective of p53status. Cytostasis and sustained G2 cell cycle arrest was achievedwithin 1 population doubling at 100 nM [% cells arrested at1%>3%>>air]. OCT1002 and hypoxia co-exposure generatedpersistent intracellular fluorescence attributable to the metaboliteOCT1001 while the prodrug OCT1002 was not retained.OCT1001 located within LNCaP-luc tumours at regions distantfrom blood vessels, persisted for >7 days, slowed tumour growthand reduced lung metastasis. A pilot study showed that a singledose OCT1002 induced a growth delay in pancreatic cancer BXPC3/SCIDmice xenografts, which are hypoxic, comparable withthat achieved by fractionated Gemcitabine treatment.Conclusion: Cytometric analyses have shown effective OCT1002activation in vitro. A quantitative relationship was found betweenthe degree of hypoxia, extent of uHAP bioreduction, persistenceof OCT1001, growth delay and first cycle G2 arrest. In vivoimaging, in a prostate cancer model that recapitulates TMHinduced by anti-androgen treatment, showed that uHAPactivation at TMH locations. The slowing of tumour growth andreduction in metastatic potential in prostate cancer together withmonotherapy efficacy in a pancreatic cancer model suggest thatOCT1002 has potential for tumour indications and in combinedmodalities where TMH is considered to be a bar

Item Type:Conference contribution (Lecture)
Keywords:OCT1002, uHAP, Prostate Cancer, Hypoxia,
Faculties and Schools:Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences
Research Institutes and Groups:Institute of Nursing and Health Research > Centre for Health and Rehabilitation Technologies
Biomedical Sciences Research Institute > Genomic Medicine
Biomedical Sciences Research Institute
ID Code:33652
Deposited By: Dr Declan McKenna
Deposited On:15 Mar 2016 09:24
Last Modified:15 Mar 2016 09:24

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