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Targeting hypoxic prostate tumours using the novel hypoxia-activated prodrug OCT1002 inhibits expression of genes associated with malignant progression

Nesbitt, Heather, Byrne, Niall M., Williams, S. Nicole, Ming, Louise, Worthington, Jenny, Errington, Rachel J., Patterson, Laurence H., Smith, Paul J., McKeown, Stephanie R. and McKenna, Declan J. 2017. Targeting hypoxic prostate tumours using the novel hypoxia-activated prodrug OCT1002 inhibits expression of genes associated with malignant progression. Clinical Cancer Research 23 (7) , pp. 1797-1808. 10.1158/1078-0432.CCR-16-1361

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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 hypoxia in vitro. In 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 vasculature in vivo. Longitudinal 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 of RUNX2 and 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: American Association for Cancer Research
ISSN: 1078-0432
Date of First Compliant Deposit: 12 February 2018
Date of Acceptance: 25 August 2016
Last Modified: 21 May 2020 11:32
URI: http://orca.cf.ac.uk/id/eprint/97090

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